Method for producing polyalkylene glycol derivative having amino group at end

ABSTRACT

A method simply produces a narrowly distributed and high-purity polyalkylene glycol derivative having an amino group at an end without using a heavy metal catalyst. A method for producing a polyalkylene glycol derivative having an amino group at the end by reacting a compound represented by the general formula (V) with an alkylene oxide, then reacting a reaction product with an electrophile represented by the general formula (I), and deprotecting the obtained product without using a heavy metal: 
       R A   3 O(R A   4 O) k−1 R A   4 O − M +   (V)
         wherein R A   3  represents a linear, branched, or cyclic hydrocarbon group having 1 to 20 carbon atoms; R A   4  represents an alkylene group having 2 to 8 carbon atoms; k represents an integer of 2 to 5; and M represents an alkali metal;       

     
       
         
         
             
             
         
       
         
         
           
             wherein R A   1a  and R A   1b  each independently represent a protective group of the amino group, or one of R A   1a  and R A   1b  represents H and the other represents a protective group of the amino group, or R A   1a  and R A   1b  bind to each other to form a cyclic protective group, and the protective group is deprotectable without using a heavy metal; R A   2  represents a linear, branched, or cyclic hydrocarbon group having 1 to 6 carbon atoms; and X represents a leaving group.

RELATED APPLICATION

This application is a divisional of U.S. patent application Ser. No.14/959,088, filed on Dec. 4, 2015, which claims priority from JapanesePatent Application No. 2014-246045, filed Dec. 4, 2014, and JapaneseApplication No. 2015-151011, filed Jul. 30, 2015, the disclosures ofwhich are incorporated by reference herein in their entirety.

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to a method for producing a polyalkyleneglycol derivative having a terminal amino group.

Recently, in drug delivery systems, a method for encapsulating drugs ina polymer micelle using a block copolymer formed from a hydrophilicsegment and a hydrophobic segment has been proposed (refer to, forexample, Japanese Patent No. 2690276, Japanese Patent No. 2777530, andJapanese Patent Application Laid-Open No. 11-335267). By using themethod, the polymer micelle functions as a carrier of drugs, producingvarious effects including sustained release of the drugs in vivo andconcentrated dosage to an affected region.

As the hydrophilic segment, many examples with use of a polyalkyleneglycol skeleton are proposed (refer to, for example, Japanese Patent No.2690276, Japanese Patent No. 2777530, and Japanese Patent ApplicationLaid-Open No. 11-335267). A compound having a polyalkylene glycolskeleton has low toxicity in vivo, and enables excretion by the kidneyto be delayed. Consequently, in comparison with a compound having nopolyalkylene glycol skeleton, the retention time in blood can beprolonged. As a result, with use of a drug micellized with apolyalkylene glycol derivative, the dosage amount or dosage frequencycan be reduced.

Among polyalkylene glycol derivatives, a compound having an amino groupat an end can lead to a block copolymer composed of a polyalkyleneglycol skeleton and an amino acid skeleton through a ring-openingpolymerization reaction with ca-amino acid-N-carboxy anhydride. Manyexamples with use of the produced block copolymer for encapsulatingdrugs in a polymer micelle are proposed (refer to, for example, JapanesePatent No. 2690276, Japanese Patent No. 2777530, and Japanese PatentApplication Laid-Open No. 11-335267).

Synthesis methods of such polyalkylene glycol derivatives having anamino group at an end are also known (refer to, for example, JapanesePatent No. 3050228 and Japanese Patent No. 3562000). In these methods,after polymerization of an alkylene oxide with use of a metal salt ofmonohydric alcohol as a polymerization initiator, a polymer end isconverted to a hydroxyl group, and then to a 2-cyanoethoxy group,finally leading to an amino group-containing substituent group(3-amino-1-propoxy group) through hydrogen reduction of the cyano group.

A polymerization example of ethylene oxide in diglyme with use of apotassium salt of substituted diethylene glycol is known, and in thisexample, in order to dissolve the metal salt in a polymerizationsolvent, an excess amount of the alcohol that is an initiator rawmaterial needs to remain during the synthesis of the metal salt. Inaddition, it is clearly disclosed that the necessary reactiontemperature is 80 to 140° C. (see Japanese Patent No. 4987719).

SUMMARY OF THE INVENTION

It is difficult to completely dissolve the metal salts of monohydricalcohol used as a polymerization initiator in polymerization solvents(organic solvents such as, for example, tetrahydrofuran (abbreviated as“THF”)) in many cases. In order to dissolve the metal salts inpolymerization solvents, an excessive amount of alcohol that is ainitiator raw material has to remain during synthesis of the metal salts(for example, in Japanese Patent No. 3050228, 13 mol of methanol to 2mol of sodium methoxide that is a polymerization initiator, and inJapanese Patent No. 4987719, 0.209 mol of diethylene glycol monomethylether to 0.024 mol of a potassium salt of diethylene glycol monomethylether that is a polymerization initiator). Due to the presence of thesealcohols in a reaction system, however, reduction in the polymerizationrate is unavoidable. Consequently, crucial reaction conditions such ashigh temperature and high pressure are required for increasing thepolymerization rate (refer to Japanese Patent No. 3050228 and JapanesePatent No. 4987719). Moreover, when the polymerization initiator doesnot dissolve in a polymerization solvent, the system does not becomeuniform, and therefore, there is a problem in that the dispersity of theobtained polyalkylene glycol derivative becomes broad becausepolymerization only progresses from the dissolved polymerizationinitiator.

Monohydric alcohols contain a trace amount of water in many cases. Thepolymerization of an alkylene oxide with a polymerization initiatorprepared in a water-containing state produces a polymer compound havinga hydroxyl group at both ends as by-product (hereinafter abbreviated as“diol polymer”). In the case of monohydric alcohols having a boilingpoint sufficiently higher than that of water, the water content can bereduced by dehydration under reduced pressure. Since methanol for use inthe case in which an end is, for example, a methyl group, has a boilingpoint lower than that of water, the water content cannot be removed bydehydration under reduced pressure. The polymerization of an alkyleneoxide with a metal salt prepared by using methanol, therefore,unavoidably produces a diol polymer. Since various physical propertiesof a diol polymer, such as structure and molecular weight, are similarto those of the target substance, it is extremely difficult to performseparation and purification. When the subsequent reactions proceed inthe presence of a diol polymer as an impurity, a polymer including anamino group at both ends is produced unless proper reaction conditionsare selected. The direct use of the polymer which includes such animpurity may make it possible that an intended performance cannot beachieved in designing a polymer micellizing agent. In the polymerizationreaction, therefore, the water content is required to be reduced to beas low as possible.

Moreover, it is known that heavy metals have an adverse effect whenexcessively stored in vivo; however, in the synthesis methods describedin Japanese Patent No. 3050228 and Japanese Patent No. 3562000, a cyanogroup is converted to an aminomethyl group through hydrogen reductionusing Raney nickel catalyst, and therefore there is concern over thepossibility that trace amounts of metals being mixed in the finalproduct. Furthermore, the reaction is generally considered to require ahigh temperature, there have been problems yet to be solved that atarget product cannot be obtained with a high yield rate because3-elimination of acrylonitrile progresses associated with reaction at ahigh temperature and that there is a risk that secondary and tertiaryamines are produced due to addition reaction of an amine to an iminethat is an intermediate in nitrile reduction.

It is an object of the present invention to provide a method for simplyproducing a narrowly distributed and high-purity polyalkylene glycolderivative having an amino group at an end under mild conditions withoutusing a heavy metal catalyst by which method the problems of theconventional technologies are solved.

Through intensive research to achieve the object, the present inventorshave found that, use of a compound, as a polymerization initiator,having a sufficient solubility in polymerization solvents accomplishesthe polymerization of an alkylene oxide under mild conditions, andfurther that reaction of the obtained polymerization product with anelectrophile the amino group which is protected can finally lead to ahigh-purity and narrowly distributed polyalkylene derivative having anamino group at an end through a simple process without using a heavymetal catalyst.

That is to say, the present invention relates to a method for producinga polyalkylene glycol derivative having an amino group at an endcontaining the following steps of (a) to (c).

(a) reacting a compound represented by the following general formula (V)with an alkylene oxide in a polymerization solvent:

R_(A) ³O(R_(A) ⁴O)_(k−1)R_(A) ⁴O⁻M⁺  (V)

-   -   wherein R_(A) ³ represents a linear hydrocarbon group having 1        to 20 carbon atoms, or a branched or cyclic hydrocarbon group        having 3 to 20 carbon atoms;    -   R_(A) ⁴ represents an alkylene group having 2 to 8 carbon atoms;    -   k represents an integer of 2 to 5; and    -   M represents an alkali metal;

(b) reacting a reaction product obtained in the step (a) with anelectrophile represented by the following general formula (I):

wherein R_(A) ^(1a) and R_(A) ^(1b) each independently represent aprotective group of the amino group, or one of R_(A) ^(1a) and R_(A)^(1b) represents a hydrogen atom and the other represents a protectivegroup of the amino group, or R_(A) ^(1a) and R_(A) ^(1b) bind to eachother to represent a cyclic protective group forming a ring togetherwith a nitrogen atom of the amino group, and the protective grouprepresents a protective group deprotectable without using a heavy metalcatalyst;

R_(A) ² represents a linear divalent hydrocarbon group having 1 to 6carbon atoms, or a branched or cyclic divalent hydrocarbon group having3 to 6 carbon atoms; and

X represents a leaving group; and

(c) deprotecting a reaction product obtained in the step (b) withoutusing a heavy metal catalyst.

The present invention, according to another embodiment, relates to amethod for producing a polyalkylene glycol derivative having an aminogroup at an end containing the following [Step 1] to [Step 4]:

wherein R_(A) ^(1a) and R_(A) ^(1b) each independently represent aprotective group of the amino group, or one of R_(A) ^(1a) and R_(A)^(1b) represents a hydrogen atom and the other represents a protectivegroup of the amino group, or R_(A) ^(1a) and R_(A) ^(1b) bind to eachother to represent a cyclic protective group forming a ring togetherwith a nitrogen atom of the amino group, and the protective grouprepresents a protective group deprotectable without using a heavy metalcatalyst;

R_(A) ² represents a linear divalent hydrocarbon group having 1 to 6carbon atoms, or a branched or cyclic divalent hydrocarbon group having3 to 6 carbon atoms;

R_(A) ³ represents a linear hydrocarbon group having 1 to 20 carbonatoms, or a branched or cyclic hydrocarbon group having 3 to 20 carbonatoms;

R_(A) ⁴ represents an alkylene group having 2 to 8 carbon atoms;

X represents a leaving group; and

n represents an integer of 3 to 450;

[Step 1]

a step of reacting a compound represented by the following generalformula (IV) with an alkali metal or an alkali metal compound selectedfrom M, M⁺H⁻, R_(X) ⁻M⁺, [R_(Y)]⁻M⁺, and R_(Z)O⁻M⁺ (wherein M representsan alkali metal, R_(X) represents an alkyl group having 1 to 20 carbonatoms or an arylalkyl group having 7 to 20 carbon atoms, R_(Y)represents an aromatic compound that may have a substituent, and R_(Z)represents an alkyl group having 1 to 6 carbon atoms) to obtain acompound represented by the following general formula (V):

R_(A) ³O(R_(A) ⁴O)_(k)H  (IV)

-   -   wherein R_(A) ³ and R_(A) ⁴ are the same as defined in the        general formulas (II) and (III) as above;    -   k represents an integer of 2 to 5;

R_(A) ³O(R_(A) ⁴O)_(k−1)R_(A) ⁴O⁻M⁺  (V)

-   -   wherein R_(A) ³, R_(A) ⁴, and k are the same as defined in the        general formula (IV) as above; and    -   M is the same as defined for the alkali metal or the alkali        metal compound as above;

[Step 2]

a step of reacting the compound represented by the general formula (V)with an alkylene oxide in a polymerization solvent to obtain a compoundrepresented by the following general formula (VI):

R_(A) ³O(R_(A) ⁴O)_(n−1)R_(A) ⁴O⁻M⁺  (VI)

-   -   wherein R_(A) ³, R_(A) ⁴, and n are the same as defined in the        general formulas (II) and (III) as above; and    -   M is the same as defined for the alkali metal or the alkali        metal compound as above;

[Step 3]

a step of reacting the compound represented by the general formula (VI)with the electrophile represented by the general formula (I) to obtainthe compound represented by the general formula (II); and

[Step 4]

a step of deprotecting the compound represented by the general formula(II) without using a heavy metal catalyst to obtain the compoundrepresented by the general formula (III).

The present invention provides a method for producing an aminogroup-containing polyethylene glycol derivative as a useful raw materialfor block copolymers for use in medical supplies and cosmetic products.By using the production method of the present invention, polymerizationperformed substantially in the absence of an alcohol, that is apolymerization initiator raw material and that is a cause of reductionin polymerization rate, becomes possible. Furthermore, thepolymerization of an alkylene oxide can be performed under milderconditions than conventional conditions, and production of impuritiessuch as a diol polymer attributable to a trace amount of water issuppressed to make it possible to produce a high-purity and narrowlydistributed polyalkylene glycol derivative by a simple process.Moreover, in the case in which the method also includes a purificationstep, since freeze drying is not needed during the purification andextraction of the polyalkylene glycol derivative, the method is furtheradvantageous in that the polyalkylene glycol derivative can be producedin an industrial scale and simplification of facilities and processescan be realized. Furthermore, by using the electrophile in which theamino group is protected, the reduction method using a heavy metal doesnot have to be used to prevent by-products being mixed, and therefore,it becomes possible to reduce a risk of mixing heavy metal impuritiesand by-products that should be avoided in medical supplies. Furthermore,since the polymerization initiator uniformly dissolves in the systemduring polymerization, the polyalkylene glycol derivative produced bythe production method according to the present invention is narrowlydistributed, capable of being extremely advantageously used in leadingto a block copolymer formed from a hydrophilic segment and a hydrophobicsegment, for use in a field of drug delivery system.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention now will be described more fully hereinafter inwhich embodiments of the invention are provided with reference to theaccompanying drawings.

This invention may, however, be embodied in many different forms andshould not be construed as limited to the embodiments set forth herein;rather, these embodiments are provided so that this disclosure will bethorough and complete, and will fully convey the scope of the inventionto those skilled in the art.

The terminology used in the description of the invention herein is forthe purpose of describing particular embodiments only and is notintended to be limiting of the invention. As used in the description ofthe invention and the appended claims, the singular forms “a”, “an” and“the” are intended to include the plural forms as well, unless thecontext clearly indicates otherwise. Unless otherwise defined, alltechnical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs. All references cited are incorporated herein byreference in their entirety.

The present invention is, according to an embodiment, a method forproducing a polyalkylene glycol derivative having an amino group at anend represented by the following general formula (III), the methodincluding the following [Step 2], [Step 3], and [Step 4]. Moreover, thepresent invention is, according to a preferable embodiment, a method forproducing a polyalkylene glycol derivative having an amino group at anend represented by the following general formula (III), the method ofsequentially performing the following [Step 1] to [Step 4]:

[Step 1]

A step of reacting a compound represented by the following generalformula (IV) with an alkali metal or an alkali metal compound selectedfrom M, M⁺H⁻, R_(X) ⁻M⁺, [R_(Y)]⁻M⁺, and R_(Z)O⁻M⁺ (wherein M representsan alkali metal, R_(X) represents an alkyl group having 1 to 20 carbonatoms or an arylalkyl group having 7 to 20 carbon atoms, R_(Y)represents an aromatic compound that may have a substituent, and R_(Z)represents an alkyl group having 1 to 6 carbon atoms) to obtain acompound represented by the following general formula (V);

[Step 2]

a step of reacting the compound represented by the general formula (V)with an alkylene oxide in a polymerization solvent to obtain a compoundrepresented by the following general formula (VI);

[Step 3]

a step of reacting the compound represented by the general formula (VI)with the electrophile represented by the general formula (I) to obtainthe compound represented by the general formula (II); and

[Step 4]

a step of deprotecting the compound represented by the general formula(II) without using a heavy metal catalyst to obtain the compoundrepresented by the general formula (III).

In the general formulas (I) and (II), R_(A) ^(1a) and R_(A) ^(1b) eachindependently represent a protective group of the amino group, or one ofR_(A) ^(1a) and R_(A) ^(1b) represents a hydrogen atom and the otherrepresents a protective group of the amino group, or R_(A) ^(1a) andR_(A) ^(1b) bind to each other to represent a cyclic protective groupforming a ring together with a nitrogen atom of the amino group, and theprotective group represents a protective group deprotectable withoutusing a heavy metal catalyst. Specific examples of R_(A) ^(1a) and R_(A)^(1b) are as described in the description of the [Step 3] below.

In the general formulas (I) to (III), R_(A) ² represents a lineardivalent hydrocarbon group having 1 to 6 carbon atoms, or a branched orcyclic divalent hydrocarbon group having 3 to 6 carbon atoms. Specificexamples of R_(A) ² include a group obtained by eliminating a hydrogenatom from each of a methyl group, an ethyl group, an n-propyl group, anisopropyl group, an n-butyl group, an isobutyl group, a tert-butylgroup, an n-pentyl group, an n-hexyl group, a cyclopropyl group, acyclobutyl group, a cyclopentyl group, and a cyclohexyl group,preferably a group obtained by eliminating a hydrogen atom from each ofthe ethyl group, and the n-propyl group.

In the general formulas (II) to (VI), R_(A) ³ represents a linearhydrocarbon group having 1 to 20 carbon atoms, or a branched or cyclichydrocarbon group having 3 to 20 carbon atoms. Specific examples ofR_(A) ³ include a methyl group, an ethyl group, an n-propyl group, anisopropyl group, an n-butyl group, an isobutyl group, a tert-butylgroup, a pentyl group, a cyclopentyl group, a hexyl group, a cyclohexylgroup, an octyl group, a decyl group, a dodecyl group, a phenyl group,an o-tolyl group, an m-tolyl group, a p-tolyl group, a 2,3-xylyl group,a 2,4-xylyl group, a 2,5-xylyl group, a 2,6-xylyl group, a 3,4-xylylgroup, a 3,5-xylyl group, a mesityl group, a vinyl group, and an allylgroup, preferably the methyl group and the ethyl group.

In the general formulas (II) to (VI), R_(A) ⁴ represents an alkylenegroup having 2 to 8 carbon atoms. Among others, alkylene groups having 2to 3 carbon atoms are preferable. That is to say, an ethylene group or apropylene group is preferable. (R_(A) ⁴O)_(n) may be composed of onekind of an oxyalkylene group, for example, only from an oxyethylenegroup or oxypropylene group, or may be two or more kinds of oxyalkylenegroups mixed together. In the case in which two or more kinds ofoxyalkylene groups are mixed together, (R_(A) ⁴O)_(n) may be formed fromtwo or more different kinds of oxyalkylene groups by randompolymerization or block polymerization.

In the general formula (I), X represents a leaving group. Specificexamples of X as the leaving group include Cl, Br, I,trifluoromethanesulfonate (hereinafter, written as “TfO”),p-toluenesulfonate (hereinafter, written as “TsO”), and methanesulfonate(hereinafter, written as “MsO”), although this is not limited thereto.

In the general formulas (II), (III), and (VI), n represents an integerof 3 to 450. Preferably n=10 to 400, more preferably n=20 to 350.

In the general formulas (IV) and (V), k=2 to 5. The repeating unit of(R_(A) ⁴O) in the general formula (V) may have an effect of enhancingsolubility to polymerization solvents, and k is preferably 2 or morefrom the viewpoint of the effect. Moreover, having k=2 to 4 is preferredconsidering that the compound represented by the general formula (IV) ismade to be of high purity and to have a boiling point at whichdistillation is possible.

In the general formulas (V) and (VI), M represents an alkali metal.Specific examples of M as the alkali metal include lithium, sodium,potassium, cesium, and sodium-potassium alloy.

The embodiments will be described below in the order of [Step 1] to[Step 4] along time series.

In the [Step 1], the compound represented by the general formula (IV) isreacted with the alkali metal or the alkali metal compound to synthesizethe compound represented by the following general formula (V).

R_(A) ³O(R_(A) ⁴O)_(k)H  (IV)

R_(A) ³O(R_(A) ⁴O)_(k−1)R_(A) ⁴O⁻M⁺  (V)

In the [Step 1], the alkali metal or the alkali metal compound to bereacted with the compound represented by the general formula (IV) meansa substance selected from the group consisting of alkali metalsrepresented by M, hydrides of alkali metals represented by M⁺H, organicalkali metals represented by R_(X) ⁻M⁺ or [R_(Y)]⁻M⁺ (R_(X) representsan alkyl group having 1 to 20 carbon atoms, or an arylalkyl group having7 to 20 carbon atoms, and R_(Y) represents an aromatic compound that mayhave a substituent), and alkali metal salts of monohydric alcoholsrepresented by R_(Z)O⁻M⁺ (R_(Z) represents an alkyl group having 1 to 6carbon atoms).

Specific examples of M as the alkali metal include lithium, sodium,potassium, cesium, and sodium-potassium alloy. Specific examples of M⁺H⁻include sodium hydride, and potassium hydride. Specific examples ofR_(X) ⁻M⁺ include ethyllithium, ethylsodium, n-butyllithium,sec-butyllithium, tert-butyllithium, 1,1-diphenylhexyllithium,1,1-diphenyl-3-methylpentyllithium, 1,1-diphenylmethylpotassium,cumylsodium, cumylpotassium, and cumylcesium. Specific examples of[R_(Y)]⁻M⁺ include lithium naphthalenide, sodium naphthalenide,potassium naphthalenide, anthracenelithium, anthracenesodium,anthracenepotassium, biphenylsodium, sodium 2-phenylnaphthalenide,phenanthrenesodium, sodium acenaphthylenide, sodium benzophenone ketyl,sodium 1-methoxynaphthalenide, potassium 1-methoxynaphthalenide, andpotassium 1-methylnaphthalenide, and these compounds may be used singlyor in combination of two or more. Specific examples of R_(Z) inR_(Z)O⁻M⁺ include a methyl group, an ethyl group, an n-propyl group, anisopropyl group, an n-butyl group, a sec-butyl group, a tert-butylgroup, an n-pentyl group, an isopentyl group, and an n-hexyl group,although this is not limited thereto. Among others, as alkali metal orthe alkali metal compound, sodium, potassium, sodium hydride, andpotassium hydride are preferred from the viewpoint that side reactionsare suppressed, and moreover, sodium naphthalenide, potassiumnaphthalenide, anthracenesodium, anthracenepotassium, sodium methoxide,potassium methoxide, sodium ethoxide, and potassium ethoxide arepreferred from the viewpoint of high reactivity.

The amount of the alkali metal, M⁺H⁻, R_(X) ⁻M⁺ or [R_(Y)]⁻M⁺ and/orR_(Z)O⁻M⁺ for use in the [Step 1] is, for example, 0.5 to 3.0equivalents, more preferably 0.8 to 2.0 equivalents, more preferably 0.9to 1.0 equivalents, relative to the number of moles of the compoundrepresented by the general formula (IV). Particularly in the case inwhich the alkali metal compound used can also function as thepolymerization initiator in the subsequent [Step 2], it is necessary tomake the amount of the alkali metal compound used 1.0 equivalent orless. Moreover, in the case in which an alkali metal compound thatproduces an alcohol after reacting with an alcohol as an initiator rawmaterial, such as, for example, potassium methoxide, it is alsonecessary to distill away methanol produced in the [Step 1] underreduced pressure after the synthesis of the compound represented by thegeneral formula (V), and it is necessary that potassium methoxideproduced through equilibrium reaction does not function as apolymerization initiator in the subsequent [Step 2].

In synthesizing the compound represented by the general formula (V) inthe [Step 1], the reaction may be performed, for example, by adding thecompound represented by the general formula (IV) and the alkali metal orthe alkali metal compound to a proper solvent and mixing, or a mixtureobtained by mixing the alkali metal or the alkali metal compound in aproper solvent may be dripped into the compound represented by thegeneral formula (IV), or the compound represented by the general formula(IV) may be dripped into a mixture obtained by mixing the alkali metalor the alkali metal compound in a proper solvent. Specific examples ofthe solvent for use in the [Step 1] include ethers such as THF and1,4-dioxane, and aromatic hydrocarbons such as benzene, toluene, andxylene. As the solvent, a solvent distilled with a dehydrating agentsuch as sodium metal may be used. The amount of the solvent used is, forexample, 1 to 50 times, preferably 2 to 10 times, more preferably 2 to 5times the mass of the compound represented by the general formula (IV),although this is not particularly limited thereto. The reaction in the[Step 1] is performed at a temperature of, for example, −78° C. to 150°C., preferably at a temperature of 0° C. to the reflux temperature ofthe solvent for use (for example, 0° C. to 66° C. as a refluxtemperature of THF). The reaction system may be cooled or heated asneeded.

Among others, as the solvent for use in the [Step 1], the same solventas will be used as the polymerization solvent in the subsequent [Step 2]is preferably used. The reason is because whether the polymerizationinitiator synthesized in the [Step 1] dissolves or not in thepolymerization solvent for use in the [Step 2] can be confirmed inadvance during the synthesis of the polymerization initiator in the[Step 1]. Specifically, the solubility of the polymerization initiatorin the polymerization solvent can be confirmed in a manner as describedbelow in the case in which, for example, THF is used as the reactionsolvent in the [Step 1], potassium hydride (for example, 1.0 equivalentor less of potassium hydride relative to the compound represented by thegeneral formula (IV)) is used as the alkali metal compound, and THF isused as the polymerization solvent in the [Step 2]. As the reaction inthe [Step 1] progresses, potassium hydride in a powder form decreasesand hydrogen is produced. By confirming whether the precipitation of asalt and the cloudiness in the reaction solution are observed or notwhen all of the potassium hydride is finally reacted, without theprecipitation of the polymerization initiator represented by the generalformula (V) produced at that time in THF that is a reaction solvent inthe [Step 1], the solubility of the polymerization initiator in thepolymerization solvent in the subsequent [Step 2] can be confirmed inadvance.

Moreover, as another method for confirming the solubility of thepolymerization initiator represented by the general formula (V) in thepolymerization solvent for use in the [Step 2], the method as describedbelow can be given as an example, though not limited thereto. Asdescribed above, the compound represented by the general formula (IV) isreacted with the alkali metal or the alkali metal compound to synthesizethe polymerization initiator represented by the general formula (V), andthen the solvent and the reagents other than the polymerizationinitiator represented by the general formula (V) may be removed by ausual method to extract the polymerization initiator represented by thegeneral formula (V). The obtained polymerization initiator representedby the general formula (V) may be dissolved in the polymerizationsolvent to be used in the subsequent [Step 2] at a concentration of, forexample, 20 wt. %, and whether the precipitation of a salt and thecloudiness are observed or not can be confirmed by visual observation.

As described above, the polymerization of an alkylene oxide with apolymerization initiator prepared with a water-containing monohydricalcohol that is a polymerization initiator raw material produces a diolpolymer as by-product. Separation of a diol polymer from the targetsubstance is extremely difficult, and it is likely that the intendedperformance of a polymer micellizing agent is not achieved with thedirect use of the polymer which contains a diol polymer or impuritiesderived therefrom. In the polymerization reaction in the subsequent[Step 2], therefore, the water content in the reaction system in whichthe compound (polymerization initiator) represented by the generalformula (V) is dissolved is preferably reduced to be as low as possible.Regarding this, a compound represented by the general formula (IV) with,for example, R_(A) ³═CH₃, R_(A) ⁴═CH₂CH₂, k=2, and a high boiling pointof 194° C., the compound being a precursor of the compound representedby the general formula (V), has a sufficient difference in boiling pointfrom water, so that separation of water can be achieved by drying underreduced pressure. Therefore, it is preferred that, prior to the reactionof the compound represented by the general formula (IV) with the alkalimetal or the alkali metal compound in the [Step 1], the compoundrepresented by the general formula (IV) be sufficiently dried underreduced pressure and then distilled. In that case, the water contentratio of the compound represented by the general formula (IV) afterdistillation may be reduced, for example, to 50 ppm or less, preferably10 ppm or less, more preferably 5 ppm or less. In this way, by reducingthe water content of the compound represented by the general formula(IV) that is a raw material of the polymer initiator as low as possible,by-production of the diol polymer can more favorably be suppressed inperforming polymerization using the obtained polymerization initiator.

In addition, the concentration of a substance (mmol/g) that can functionas a polymerization initiator in a reaction solution (reaction solutionafter synthesis of the polymerization initiator) after completion of the[Step 1] can be determined from the amount of substance of the rawmaterial alcohol for use in the [Step 1] and represented by the generalformula (IV) and the total weight of the reaction solution aftercompletion of the [Step 1]. That is to say, the concentration of thesubstance that can function as the polymerization initiator in thereaction solution after completion of the [Step 1] can be determined by“amount of substance of raw material alcohol (IV) used (mmol)/totalweight of reaction solution (g) after completion of [Step 1]”. Thereason is because the raw material alcohol also functions as thepolymerization initiator in the case in which the raw material alcoholrepresented by the general formula (IV) is left in the reaction solutionafter completion of the [Step 1]. (The reaction in the [Step 2] isequilibrium reaction, and therefore the compound represented the generalformula (V) reacts as the polymerization initiator to produce a polymer,and an alkoxide at an end of the polymer eliminates a proton of the rawmaterial alcohol (IV) to allow the raw material alcohol to function asan alkoxide (polymerization initiator).) However, as will be describedlater, the residual amount of the raw material alcohol in the reactionsolution after completion of the [Step 1] is preferably as small aspossible. The reaction solution after completion of the [Step 1] may beused as it is as a polymerization initiator solution in the subsequent[Step 2].

Conventionally, generally used polymerization initiators do not dissolvealone in polymerization solvents such as THF in many cases. For example,in the case in which polymerization of an alkylene oxide is performed inTHF, CH₃O⁻M⁺ (M represents an alkali metal) that has conventionally beenused when a methyl group is intended to be an end of polymerization doesnot singly dissolve in THF. Therefore, in the conventional method, inorder to dissolve the polymerization initiator in the polymerizationsolvent to uniformly perform polymerization, it is necessary to use anexcessive amount of methanol that is an alcohol as an initiator rawmaterial. Due to the excessive presence of these alcohols in a reactionsystem, however, reduction in the polymerization rate is unavoidable.Consequently, crucial reaction conditions such as high temperature andhigh pressure are required for increasing the polymerization rate in theconventional method. In contrast, the compound represented by thegeneral formula (V) for use as a polymerization initiator in the presentinvention is easily dissolved in the polymerization solvent such as THFwithout requiring an alcohol as an initiator raw material, enablingpolymerization under mild conditions.

In this way, in order to obtain a sufficient polymerization rate undermild conditions in the subsequent [Step 2], a polymerization initiatorhaving a small amount of a residual alcohol is preferably synthesized inthe [Step 1]. Specifically, the ratio of the amounts of substancesbetween the polymerization initiator represented by the general formula(V) and the alcohol that is an initiator raw material represented by thegeneral formula (IV) is preferably 100:0 to 80:20 (mol %) aftersynthesis of the polymerization initiator represented by the generalformula (V) from the alcohol as an initiator raw material represented bythe general formula (IV), and more preferably reaction is performed sothat the ratio is 100:0 to 90:10 (mol %). In order to achieve that, the[Step 1] is preferably performed under conditions so that the number ofmoles of the alkali metal or the alkali metal compound used is, forexample, 0.8 to 1.5 times, preferably 0.9 to 1.0 times the number ofmoles of the compound used and represented by the general formula (IV).That is to say, a reaction product that has a small amount of residualalcohol as an initiator raw material is preferably obtained in the [Step1].

Moreover, it is possible to distill away the alcohol represented by thegeneral formula (IV) under reduced pressure after synthesis of thepolymerization initiator represented by the general formula (V). In thatcase, the raw material alcohol is preferably removed until the ratio ofthe amounts of substances between the polymerization initiatorrepresented by the general formula (V) and the alcohol represented bythe general formula (IV) is 100:0 to 98:2 (mol %) after completion ofthe [Step 1], and more preferably the raw material alcohol is removeduntil the ratio is 100:0 to 99:1 (mol %). By reducing the amount of theresidual raw material alcohol, it is possible to increase thepolymerization rate in the subsequent [Step 2] more.

In the production method of the present invention, as described above,even when the alcohol compound, that is an initiator raw material andthat is represented by the general formula (IV) and that is a factor ofincreasing the solubility of the polymerization initiator inpolymerization solvents, and, on the other hand, also a factor ofreducing the polymerization rate, is not left, it is possible todissolve the compound represented by the general formula (V) as apolymerization initiator in polymerization solvents. A structure thatplays the role is a repeating unit of (R_(A) ⁴O) in the general formula(V), and the compatibility between the polymerization initiator and thepolymerization solvent is enhanced by the polymerization initiatorhaving the structure, making it possible to dissolve the polymerizationinitiator in the polymerization solvent without a substantial presenceof the alcohol. As a result thereof, polymerization in a uniform systembecomes possible, and production of a narrowly distributed polyalkyleneglycol derivative under mild conditions becomes possible.

In the [Step 2], the compound represented by the general formula (V)(polymerization initiator) is reacted with an alkylene oxide in thepolymerization solvent to synthesize the compound represented by thefollowing general formula (VI).

R_(A) ³O(R_(A) ⁴O)_(n−1)R_(A) ⁴O⁻M⁺  (VI)

In the [Step 2], the compound represented by the general formula (V) maybe reacted with an alkylene oxide after the compound represented by thegeneral formula (V) is completely dissolved in the polymerizationsolvent. As described above, the compound represented by the generalformula (V) can be easily soluble to the polymerization solvent evenwhen the compound represented by the general formula (IV) that is theraw material alcohol is not substantially present. That the compoundrepresented by the general formula (V) can completely be dissolved inthe polymerization solvent can be confirmed by, for example, the factthat the precipitation of a salt or cloudiness is not observed in thepolymerization solvent by visual observation. In this case, theprecipitation of a salt and the cloudiness are not desirably observed ina state in which the mass of the polymerization solvent is equal to orless than 10 times (and equal to or more than 1 times) the mass of thecompound represented by the general formula (V). That is to say, theprecipitation of a salt and the cloudiness are not desirably observed ina state in which the concentration of the compound represented by thegeneral formula (V) in the polymerization solvent solution is 9.1 wt. %or more (and 50 wt. % or less). After confirming that the compoundrepresented by the general formula (V) completely dissolves in thepolymerization solvent as described above, the polymerization solventsolution containing the compound represented by the general formula (V)may be used for polymerization reaction keeping the concentration as itis during the confirmation, or may be used for polymerization reactionin a diluted state by further adding the polymerization solvent. Inaddition, the amount of the polymerization solvent may be adjusted so asto be, for example, 1 to 50 times, preferably 2 to 25 times, the mass ofthe alkylene oxide used at the time of starting the polymerizationreaction.

Furthermore, as described above, the presence of the raw materialalcohol becomes the factor of reducing the polymerization rate, andtherefore the polymerization initiator is preferably used in a state inwhich the amount of the raw material alcohol is small in the [Step 2].For example, a reaction mixture containing the polymerization initiatorrepresented by the general formula (V) obtained in the [Step 1] and theraw material alcohol represented by the general formula (IV) preferablyin a ratio of the amounts of substances of 100:0 to 80:20 is preferablydissolved directly in the polymerization solvent to use.

As the polymerization solvent for use in the [Step 2], cyclic ethercompounds having 4 to 10 carbon atoms or linear or branched ethercompounds are preferably used from the viewpoint that the compatibilitywith the polymerization initiator is high. Specific examples of thecyclic ether compound includes furan, 2,3-dihydrofuran,2,5-dihydrofuran, 2,3-dimethylfuran, 2,5-dimethylfuran, tetrahydrofuran(THF), 2-methyltetrahydrofuran, 3-methyltetrahydrofuran,2,5-dimethyltetrahydrofuran, 1,2-methylenedioxybenzene, 1,3-dioxolane,2-methyl-1,3-dioxolane, 4-methyl-1,3-dioxolane,2,2-dimethyl-1,3-dioxolane, 3,4-dihydroxy-2H-pyran, tetrahydropyran,1,3-dioxane, 1,4-dioxane, 2,4-dimethyl-1,3-dioxane, 1,4-benzodioxane,1,3,5-trioxane, and oxepane, although this is not limited thereto.Specific examples of the linear or branched ether compound includemonoethylene glycol dimethyl ether, diethylene glycol dimethyl ether,and triethylene glycol dimethyl ether, though not limited thereto. THFin particular is preferably used. Moreover, organic solvents other thanthe ether compounds may be used, and specific examples thereof includearomatic hydrocarbons such as benzene, toluene, and xylene, though notlimited thereto. The organic solvent for use may be a single solvent, ormay be used in combination of two or more. In the case in which theorganic solvents are used in combination, the combination and the mixingratio is not particularly limited.

The amount of the polymerization solvent used for polymerizationreaction is, for example, 1 to 50 times, preferably 2 to 30 times, morepreferably 3 to 20 times the mass of the alkylene oxide used, althoughthis is not particularly limited. The polymerization solvent distilledwith a dehydrating agent such as metal sodium is preferably used. Thewater content of the polymerization solvent is, for example, 50 ppm orless, preferably 10 ppm or less, more preferably 5 ppm or less.

Specific example of the alkylene oxide used includes ethylene oxide,propylene oxide, and butylene oxide. Among them, ethylene oxide andpropylene oxide that are easily polymerized are preferred. The ratio ofamounts of use between the compound represented by the general formula(V) and the alkylene oxide used for polymerization reaction is, forexample, 1:1 to 1:448, preferably 1:10 to 1:400 as the ratio of theamounts of substances of the compound represented by the general formula(V): the alkylene oxide, although this is not particularly limitedthereto.

In the [Step 2], the alkylene oxide may be added in one batch to areaction system with the compound represented by the general formula (V)dissolved in the polymerization solvent, or a solution of the alkyleneoxide dissolved in the polymerization solvent may be dripped into thereaction system. The polymerization reaction is performed at atemperature of, for example, 30° C. to 60° C., preferably 40° C. to 60°C., more preferably 45° C. to 60° C. The pressure during thepolymerization reaction is, for example, 1.0 MPa or less, preferably 0.5MPa or less. The degree of progress of polymerization reaction can bemonitored with GPC, and when no change is observed in conversion ratioof the alkylene oxide, the completion can be assumed. The compoundrepresented by the general formula (V) for use as a polymerizationinitiator in the present invention can be easily dissolved in thepolymerization solvent as described above and requires no alcohol thatis an initiator raw material, and thus does not require crucial reactionconditions such as high temperature and high pressure during thepolymerization, enabling polymerization under mild conditions. Asdescribed above, use of the polymerization initiator represented by thegeneral formula (V) makes it possible to obtain the polyalkylene glycolderivative represented by the general formula (VI) in the polymerizationunder mild conditions. Accordingly, the present invention also relatesto a method for producing a polyalkylene glycol derivative representedby the general formula (VI) using a polymerization initiator representedby the general formula (V) (preferably including [Step 1] and [Step 2]).

In the [Step 3], the compound obtained in the preceding [Step 2] andrepresented by the general formula (VI) is reacted with the electrophilerepresented by the following formula (I) to synthesize the compoundrepresented by the general formula (II).

Preferably, in the [Step 3], an unpurified compound represented by thegeneral formula (VI) obtained in the [Step 2] is directly used for thereaction with the electrophile represented by the general formula (I).This not only achieves cost reduction due to simplification of theseparation purifying process, but also has an advantage of preventingreduction in yield rate due to purifying operation (polymer adhering tomanufacturing equipment, dissolving in a poor solvent, and the like).

That is to say, in the [Step 3], the reaction liquid containing thecompound represented by the general formula (VI) after completion of the[Step 2] may be directly used, or may be concentrated for use. In thecase of concentration of the reaction liquid, the concentration of thecompound represented by the general formula (VI) is concentrated to, forexample, 10 to 50 mass %, preferably 15 to 45 mass %, more preferably 20to 40 mass %. In the reaction in the [Step 3], the electrophilerepresented by the general formula (I) is added to the reaction liquidor concentrated liquid after completion of the [Step 2] to be reacted.As the addition method of the electrophile represented by the generalformula (I) to a reaction system, the electrophile represented by thegeneral formula (I) may be added in one batch to the reaction system, ora solution of the electrophile represented by the general formula (I)dissolved in an proper solvent may be dripped into the reaction system.Examples of the solvent used in this case include the same solvents asexemplified as the polymerization solvent in the [Step 2]. The amount ofthe electrophile represented by the general formula (I) used in thisreaction is, for example, 1 to 20 equivalents, preferably 1 to 5equivalents, more preferably 1 to 3 equivalents, relative to the numberof moles of the compound represented by the general formula (VI).

Although the reaction in the [Step 3] proceeds without a catalyst, abasic compound may be added for further acceleration of the reaction. Inthat case, examples of the basic compound include potassium hydroxide,sodium hydroxide, and potassium tert-butoxide, though not limitedthereto. The amount of the basic compound added is, for example, 1 to 10equivalents, preferably 1 to 5 equivalents, more preferably 1 to 2equivalents, relative to the number of moles of the compound representedby the general formula (VI).

In the [Step 3], the reaction is performed at a temperature of, forexample, 30° C. to 60° C., preferably 30° C. to 50° C., more preferably30° C. to 45° C. The reaction is monitored by NMR, and the completioncan be assumed when no change is observed in conversion ratio.

In the [Step 3], the electrophile represented by the general formula (I)(sometimes referred to as “electrophile (I)” in the present Description)is used for the reaction with the compound represented by the generalformula (VI) as described above. Since the compound represented by thegeneral formula (I) is used as an electrophile in the [Step 3], there isan advantage that the nucleophilic reaction of the compound representedby the general formula (VI) may be completed only by using a relativelysmall amount of the electrophile. On the other hand, in the case inwhich acrylonitrile is used as an electrophile as in conventionaltechnologies, a large excessive amount of the electrophile becomesnecessary in some cases in order to allow the nucleophilic reaction ofthe compound represented by the general formula (VI) to progress up to100%, and there is a possibility that polyacrylonitrile is by-produced.However such by-product is not produced in the present invention.

The electrophile (I) for use in the [Step 3] has an amino groupprotected by a protective group that may be deprotected without using aheavy metal catalyst as described above. Examples of the electrophile(I) may be given, for example, as classified into the followingpreferred electrophiles (I-I) to (I-IV) depending on the kind of theprotective group represented by R_(A) ^(1a) and R_(A) ^(1b) in thegeneral formula (I), though not limited thereto.

The electrophile (I-I) is an electrophile in the case in which R_(A)^(1a) and R_(A) ^(1b) in the general formula (I) each independentlyrepresent a protective group of the amino group, or one of R_(A) ^(1a)and R_(A) ^(1b) is a hydrogen atom and the other is a protective groupof the amino group, and is an electrophile in the case in which R_(A)^(1a) and/or R_(A) ^(1b) are a protective group having a structurerepresented by Si(R¹)₃ (trialkylsilyl group).

In the structure represented by Si(R¹)₃, R¹ each independently representa linear monovalent hydrocarbon group having 1 to 6 carbon atoms, or abranched or cyclic monovalent hydrocarbon group having 3 to 6 carbonatoms, or R¹ may bind to each other to form a 3 to 6 membered ringtogether with a silicon atom having bonds with R¹. Examples of R¹include a methyl group, an ethyl group, an n-propyl group, an isopropylgroup, an n-butyl group, an isobutyl group, a tert-butyl group, ann-pentyl group, an n-hexyl group, a cyclopropyl group, a cyclobutylgroup, a cyclopentyl group, and a cyclohexyl group. Moreover, in thecase in which R¹ bind to each other to form a ring together with asilicon atom, examples of R¹ include a group obtained by a hydrogen atombeing eliminated from the above-listed groups.

Preferred specific examples of the protective group having a structurerepresented by Si(R¹)₃ include a trimethylsilyl group, a triethylsilylgroup, and a tert-butyldimethylsilyl group, though not limited thereto.

The electrophile (I-II) is an electrophile in the cases in which R_(A)^(1a) and R_(A) ^(1b) in the general formula (I) each independentlyrepresent a protective group of the amino group, or one of R_(A) ^(1a)and R_(A) ^(1b) is a hydrogen atom and the other is a protective groupof the amino group, and is an electrophile in the case in which R_(A)^(1a) and/or R_(A) ^(1b) are a protective group having a structurerepresented by R_(A) ⁶OCO.

In the structure represented by R_(A) ⁶OCO, R_(A) ⁶ represents a residueof a monovalent hydrocarbon having 1 to 20 carbon atoms, and the residuemay contain a halogen atom, an oxygen atom, a nitrogen atom, a sulfuratom, a silicon atom, a phosphorus atom, or a boron atom.

Specific examples of the protective group having a structure representedby the formula R_(A) ⁶OCO include a methyloxycarbonyl group, anethyloxycarbonyl group, an isobutyloxycarbonyl group, atert-butyloxycarbonyl group, a tert-amyloxycarbonyl group, a2,2,2-trichloroethyloxycarbonyl group, a 2-trimethylsilylethyloxycarboyl group, a phenylethyloxycarbonyl group, a1-(1-adamantyl)-1-methylethyloxycarbonyl group, a1,1-dimethyl-2-haloethyloxycarbonyl group, a1,1-dimethyl-2,2-dibromoethyloxycarbonyl group, a1,1-dimethyl-2,2,2-trichloroethyloxycarbonyl group, a1-methyl-1-(4-biphenyl)ethyloxycarbonyl group, a1-(3,5-di-t-butylphenyl)-1-methylethyloxycarbonyl group, a2-(2′-pyridyl)ethyloxycarbonyl group, a 2-(4′-pyridyl)ethyloxycarbonylgroup, a 2-(N,N-dicyclohexylcarboxyamide)ethyloxycarbonyl group, a1-adamantyloxycarbonyl group, a vinyloxycarbonyl group, anallyloxycarbonyl group, a 1-isopropylallyloxycarbonyl group, acinnamyloxycarbonyl group, a 4-nitrocinnamyloxycarbonyl group, a8-quinolyloxycarbonyl group, a N-hydroxypiperidinyloxycarbonyl group, analkyldithiocarbonyl group, a benzyloxycarbonyl group, ap-methoxybenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, ap-bromobenzyloxycarbonyl group, a p-chlorobenzyloxycarbonyl group, a2,4-dichlorobenzyloxycarbonyl group, a 4-methylsulfinylbezyloxycarbonylgroup, a 9-anthrylmethyloxycarbonyl group, a diphenylmethyloxycarbonylgroup, a 9-fluorenylmethyloxycarbonyl group, a9-(2,7-dibromo)fluorenylmethyloxycarbonyl group, a2,7-di-t-butyl-[9-(10,10-dioxo-thioxanthenyl)]methyloxycarbonyl group, a4-methoxyphenyloxycarbonyl group, a 2-methylthioethyloxycarbonyl group,a 2-methyl sulfonylethyloxycarbonyl group, a2-(p-toluenesulfonyl)ethyloxycarbonyl group, a[2-(1,3-dithianyl)]methyloxycarbonyl group, a4-methylthiophenyloxycarbonyl group, a 2,4-dimethylthiophenyloxycarbonylgroup, a 2-phosphonioethyloxycarbonyl group, a 2-triphenylphosphonioisopropyloxycarbonyl group, a 1,1-dimethyl-2-cyanoethyloxycarbonyl group,an m-chloro-p-acyloxybenzyloxycarbonyl group, ap-(dihydroxyboryl)benzyloxycarbonyl group, a5-benzoisooxazolylmethyloxycarbonyl group, a2-(trifluoromethyl)-6-chromonylmethyloxycarbonyl group, aphenyloxycarbonyl group, an m-nitrophenyloxycarbonyl group, a3,5-dimethoxybenzyloxycarbonyl group, an o-nitrobenzyloxycarbonyl group,a 3,4-dimethoxy-6-nitrobenzyloxycarbonyl group, and aphenyl(o-nitrophenyl)methyloxycarbonyl group. Among them, thetert-butyloxycarbonyl group, the 2,2,2-trichloroethyloxycarbonyl group,the allyloxycarbonyl group, the benzyloxycarbonyl group, and the9-flurorenylmethyloxycarbonyl group are preferred.

The electrophile (I-III) is an electrophile in the case in which R_(A)^(1a) and R_(A) ^(1b) in the general formula (I) bind to each other torepresent a cyclic protective group forming a ring together with anitrogen atom of the amino group. Examples of the cyclic protectivegroup in such an electrophile (I-III) include an N-phthaloyl group, anN-tetrachlorophthaloyl group, an N-4-nitrophthaloyl group, anN-dithiasucciloyl group, an N-2,3-diphenylmaleoyl group, anN-2,5-dimethylpyrrolyl group, an N-2,5-bis(triosopropyloxy)pyrrolylgroup, an N-1,1,3,3-tetramethyl-1,3-disilaisoindolyl group, a3,5-dinitro-4-pyridonyl group, a 1,3,5-dioxazinyl group, and a2,2,5,5-tetramethyl-2,5-disila-1-azacyclopentane, although this is notlimited thereto. Among them, the N-phthaloyl group is preferred.

The electrophile (I-IV) is an electrophile in the case other than: thecase in which R_(A) ^(1a) and/or R_(A) ^(1b) represent the protectivegroup of the electrophile (I-I) (protective group represented bySi(R¹)₃); the case in which R_(A) ^(1a) and/or R_(A) ^(1b) represent theprotective group of the electrophile (I-II) (protective group havingstructure represented by R_(A) ⁶OCO); and the case in which R_(A) ^(1a)and/or R_(A) ^(1b) represent the protective group of the electrophile(I-III) (a cyclic protective group in which R_(A) ^(1a) and R_(A) ^(1b)bind to each other and form a ring together with a nitrogen atom).

Examples of the protective group in such an electrophile (I-IV) includea benzyl group, a p-methoxybenzyl group, a p-toluenesulfonyl group, a2-nitrobenzenesulfonyl group, a (2-trimethylsilyl)ethanesulfonyl group,an allyl group, a pivaloyl group, a methoxymethyl group, adi(4-methoxyphenyl)methyl group, a 5-benzosuberyl group, a trinylmethylgroup, a (4-methoxyphenyl)diphenylmethyl group, a 9-phenylfluorenylgroup, a [2-(trimethylsilyl)ethoxy]methyl group, and anN-3-acetoxypropyl group, although this is not limited to the protectivegroups. Among them, the benzyl group, the p-toluenesulfonyl group,2-nitrobenzenesulfonyl group, and the allyl group are preferred.

The electrophile represented by the general formula (I) is preferablyany one of the electrophiles (I-I) to (I-IV), and, among them, theelectrophile represented by the general formula (I-I-I) is preferred.That is to say, the electrophile represented by the general formula (I)where R_(A) ^(1a) and R_(A) ^(1b) each independently represent atrialkylsilyl group is more preferred. Since both of the protectivegroups of the amino group are the trialkylsilyl groups, there is anadvantage that deprotection in the subsequent [Step 4] is easy and theelectrophile is stable in the basic reaction liquid in the [Step 3].Moreover, there is also an advantage that the electrophile does not havea hydrogen atom as R_(A) ^(1a) or R_(A) ^(1b) and therefore unnecessaryreaction is difficult to occur. Therefore, it becomes possible to moresimply and stably produce a narrowly distributed and high-puritypolyalkylene glycol derivative.

(in the general formula (I-I-I), R¹ is the same as R¹ in theelectrophile (I-I), and R_(A) ² and X are the same as R_(A) ² and X inthe general formula (I))

The electrophiles (I-I) to (I-IV) may be synthesized by variousconventionally known methods. Examples of the method for synthesizingthe electrophile (I-I) include protecting the amino group of an aminehaving a leaving group with a silylating agent. Specific examples of theamine having a leaving group include halogenated amines such as3-bromopropylamine hydrobromate, and 3-chloropropylamine hydrochloricacid salt, although this is not limited thereto. Specific examples ofthe silylating agent include chlorotrimethylsilane, chlorotriethylsilane, trimethylsilyl trifluoromethanesulfonate, and triethylsilyltrifluoromethanesulfonate (hereinafter, written as “TESOTf”), though notlimited thereto.

Examples of another method for synthesizing the electrophile (I-I)include a method in which an alcohol the amino group of which issilyl-protected is reacted with a sulfonic halide to convert a hydroxygroup at an end to a leaving group. Specific examples of the alcohol theamino group of which is silyl-protected include3-bis(trimethylsilyl)amino-1-propanol, and3-bis(triethylsilyl)amino-1-propanol, though not limited thereto.Specific examples of the sulfonic halide include p-toluenesulfonylchloride (hereinafter, written as “TsCl”), and methanesulfonyl chloride(hereinafter, written as “MsCl”), though not limited thereto.

Examples of the method for synthesizing the electrophile (I-II) includeprotecting the amino group of an amine having a leaving group with acarbamating agent, although this is not limited thereto. Specificexamples of the amine having a leaving group include halogenated aminessuch as 3-bromopropylamine hydrobromate, and 3-chloropropylaminehydrochloric acid salt, though not limited thereto. Specific examples ofthe carbamating agent include di-tert-butyl dicarbonate, benzylchloroformate, fluorenylmethyl chloroformate, 2,2,2-trichloroethylchloroformate, and allyl chloroformate, though not limited thereto.

Examples of the method for synthesizing the electrophile (I-III) includea method in which an amino alcohol is reacted with a cyclic acidanhydride, and a cyclic imide alcohol produced is reacted with asulfonic halide to convert a hydroxy group at an end to a leaving group,though not limited thereto. Specific examples of the cyclic acidanhydride include phthalic anhydride, specific examples of the aminoalcohol include 3-amino-1-propanol, and specific examples of the cyclicimide alcohol include N-(3-hydroxypropyl)phthalimide, though not limitedthereto. Specific examples of the sulfonic halide include TsCl, andMsCl, though not limited thereto.

Examples of the method for synthesizing the electrophile (I-IV) includea method in which an amino alcohol is reacted with correspondingprotective groups each having a leaving group, and a protected aminoalcohol produced is reacted with a sulfonic halide to convert a hydroxygroup at an end to a leaving group, though not limited thereto. Specificexamples of the protective group having a leaving group include benzylbromide, TsCl, 2-nitrobenzene sulfonyl chloride, and allyl bromide,specific examples of the amino alcohol include 3-amino-1-propanol, andspecific examples of the protected amino alcohol include3-bisbenzylamino-1-propanol, 3-bis(p-toluenesulfonyl)amino-1-propanol,and 3-bis(nitrobenzenesulfonyl)amino-1-propanol,3-bisallylamino-1-propanol, although this is not limited thereto.

The compound represented by the general formula (II) which is a reactionproduct of the [Step 3] may be extracted as a solid from the reactionliquid for use prior to the subsequent step. In that case, the reactionliquid after completion of the [Step 3] is, either directly or afterconcentration, dripped into a poor solvent to perform crystallization ofthe compound represented by the general formula (II). In the case ofconcentration, the concentration of the compound represented by thegeneral formula (II) is adjusted to be, for example, 10 to 50 mass %,preferably 15 to 45 mass %, more preferably 20 to 40 mass %. Moreover, asalt produced through etherification reaction may be removed from thereaction liquid by filtration prior to crystallization to preventimpurities from mixing, so that a high-purity compound represented bythe general formula (II) may be extracted.

The process of removing the salt produced through etherificationreaction in the [Step 3] from the reaction liquid by filtration maydirectly be performed in the reaction solvent, or may be performed aftersolvent substitution with a good solvent. In that case, specificexamples of the good solvent include ethers such as THF and 1,4-dioxane,aromatic hydrocarbons such as benzene, toluene, and xylene, esters suchas ethyl acetate, n-butyl acetate, and y-butyrolactone, ketones such asacetone, methyl ethyl ketone, and methyl isobutyl ketone, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), and acetonitrile, thoughnot limited thereto. Use of a solvent in which a salt is easy toprecipitate may reduce salts that remain in a polymer, and thereforearomatic hydrocarbons such as benzene, toluene, and xylene arepreferred. These solvents may be used singly or in combinations of twoor more. In that case, the mixing ratio is not particularly limited.

The polymer produced in the [Step 3] contains a large amount of oxygenatoms in the structure, and therefore a salt produced in theetherification reaction is incorporated in the polymer in some cases. Inthat case, the salt may be removed using an adsorption material. As theadsorption material, an aluminum hydroxide (e.g. “KYOWADO 200” made byKyowa Chemical Industry Co., Ltd.), a synthesized hydrotalcite (e.g.“KYOWADO 500” made by Kyowa Chemical Industry Co., Ltd.), a synthesizedmagnesium silicate (e.g. “KYOWADO 600” made by Kyowa Chemical IndustryCo., Ltd.), a synthesized aluminum silicate (e.g. “KYOWADO 700” made byKyowa Chemical Industry Co., Ltd.), and an aluminum oxide/magnesiumoxide solid solution (e.g. “KW-2000” made by Kyowa Chemical IndustryCo., Ltd. and “TOMITA AD 700NS” made by Tomita Pharmaceutical Co., Ltd.)are used, however the adsorption material is not limited thereto as longas the material has performance with which a salt can be removed. Amongthem, KW-2000 is preferred because of high ion trapping ability. Theamount of the adsorption material used is, for example, 0.01 to 10times, preferably 0.1 to 8 times, more preferably 0.3 to 6 times themass of the compound represented by the general formula (II), althoughthis is not particularly limited thereto. An adsorbent may be directlyfed into the reaction liquid at the time of completion of the reactionof the compound represented by the general formula (IV) with theelectrophile represented by the general formula (I), or may be fed intothe reaction liquid after the reaction is completed and the producedalkali metal salt is filtered. The adsorbent may be removed byfiltration after the reaction was performed for 0.5 to 6 hours afterfeeding the adsorbent, however the reaction time is not particularlylimited. As a method of using the adsorption material, the adsorptionmaterial may be used as a batch system and added into the reactionsolution to perform stirring, or the adsorption material may be used asa column system and the reaction solution may be allowed to pass througha column where the adsorption material is filled. Specific example ofthe solvent in the case of performing adsorption treatment includeethers such as THF and 1,4-dioxane, aromatic hydrocarbons such asbenzene, toluene, and xylene, esters such as ethyl acetate, n-butylacetate, and y-butyrolactone, ketones such as acetone, methyl ethylketone, and methyl isobutyl ketone, dimethyl sulfoxide (DMSO),N,N-dimethylformamide (DMF), and acetonitrile, although this is notlimited thereto. The aromatic hydrocarbons such as benzene, toluene, andxylene are preferred for the purpose of enhancing the ability ofadsorbing salts. These solvents may be used singly or in combinations oftwo or more. In that case, the mixing ratio is not particularly limited.

The unpurified compound represented by the general formula (IV) producedin the [Step 2] is preferably used directly for the reaction with theelectrophile (I) in the [Step 3] as described above from the viewpointof simplifying the processes (“embodiment not through purification”).That is to say, the electrophile (I) is preferably reacted in a state inwhich an anion is left after the [Step 2]. In this case, the compoundrepresented by the general formula (II) is synthesized directly from thecompound represented by the general formula (VI) as represented by(VI)→(II).

Alternatively, in the [Step 3], the reaction of the compound representedby the general formula (VI) produced in the [Step 2] is stopped with anacid compound or the like, the compound represented by the generalformula (IX) obtained by the reaction is then purified, and is reactedwith the electrophile (I), so that the compound represented by thegeneral formula (II) may also be synthesized (“embodiment throughpurification”). That is to say, the electrophile (I) may be reactedafter the reaction of the anion is once stopped with an acid or the likeafter the [Step 2]. Specifically, the reaction of the compoundrepresented by the general formula (VI) is stopped by adding an acidcompound or the like to the reaction liquid after completion of the[Step 2] to convert the compound represented by the general formula (VI)to the compound represented by the following general formula (IX).Subsequently, the produced compound represented by the following generalformula (IX) is purified by, for example, crystallization performed bydripping into a poor solvent, and is extracted from the reaction system.Subsequently, the compound represented by the following general formula(IX) after purification thus extracted is reacted with the electrophile(I) under the presence of a basic compound, so that the compoundrepresented by the general formula (II) may be produced. In this case,the compound represented by the following general formula (IX) isconverted back again to the compound represented by the general formula(VI) through the reaction with the basic compound, and thereafter isreacted with the electrophile (I). That is to say, the compoundrepresented by the general formula (II) is synthesized from the compoundrepresented by the general formula (VI) via the compound represented bythe general formula (IX) as represented by (VI)→(IX)→(VI)→(II).

H—(OR_(A) ⁴)_(n)—OR_(A) ³  (IX)

(in the general formula (IX), R_(A) ³, R_(A) ⁴, and n are the same asR_(A) ³, R_(A) ⁴, and n in the general formulas (II) and (III))

In the embodiment through purification, whether the obtained compoundrepresented by the general formula (IX) was able to be synthesized as aproduct as desired through the polymerization in the [Step 2] may beconfirmed after stopping the reaction by, for example, performinganalysis by 1H-NMR. Moreover, the reaction with the electrophile (I) isperformed after a low molecular weight compound produced in thepolymerization is removed from the reaction system by crystallizationperformed by dripping into a poor solvent, so that the conversion of thelow molecular weight compound to a compound having an amino groupthrough the reaction with the electrophile (I) can be prevented.

Specific examples of the acid compound for use in stopping of thereaction include carboxylic acids such as formic acid, acetic acid,propionic acid, succinic acid, citric acid, tartaric acid, fumaric acid,malic acid, and trifluoroacetic acid, inorganic acids such ashydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, andperchloric acid, and sulfonic acids such as benzenesulfonic acid andp-toluenesulfonic acid, and solid acids such as AMBERLYST SERIES made byOrgano Corporation, although this is not limited thereto. The amount ofthe acid compound used is, for example, 1 to 10 equivalents, preferably1 to 5 equivalents, more preferably 1 to 2 equivalents, relative to thenumber of moles of a compound represented by the general formula (VI).These acid compounds may be used singly or in combinations of two ormore. In that case, the mixing ratio is not particularly limited.

Alternatively, the reaction may be stopped by combinations of a proticcompound such as an alcohol and water and a basic adsorption material.Specific examples of the protic compound include methanol, ethanol,n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol,tert-butyl alcohol, and water, although this is not limited thereto. Theamount of the protic compound used is, for example, 1 to 10 equivalents,preferably 1 to 5 equivalents, more preferably 1 to 2 equivalents,relative to the number of moles of the compound represented by thegeneral formula (VI). These protic compounds may be used singly or incombinations of two or more. In that case, the mixing ratio is notparticularly limited. Adsorption materials as described in the [Step 3]may be used, though not particularly limited thereto. The amount of theadsorbent used is, for example, 0.01 to 10 times, preferably 0.02 to 1time, more preferably 0.03 to 0.5 times the mass of the compoundrepresented by the general formula (VI), though not particularlylimited.

Crystallization may be performed with a poor solvent directly afterstopping the reaction, or crystallization may be performed after solventsubstitution with a good solvent. In that case, specific examples of thegood solvent include ethers such as THF and 1,4-dioxane, aromatichydrocarbons such as benzene, toluene, and xylene, esters such as ethylacetate, n-butyl acetate, and y-butyrolactone, ketones such as acetone,methyl ethyl ketone, and methyl isobutyl ketone, dimethyl sulfoxide(DMSO), N,N-dimethylformamide (DMF), and acetonitrile, although this isnot limited thereto. These solvents may be used singly or incombinations of two or more. In that case, the mixing ratio is notparticularly limited. The concentration of the compound represented bythe general formula (IX) after solvent substitution is, for example, 10to 50 mass %, preferably 15 to 45 mass %, more preferably 20 to 40 mass%.

The poor solvent for use has a low solubility for the compoundrepresented by the general formula (IX). Specific examples of thesuitable poor solvent include hydrocarbon such as hexane, heptane,octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, andcyclooctane, and ethers such as diethyl ether, diisopropyl ether, anddi-n-butyl ether. The amount of the poor solvent used is, for example, 5to 100 times, preferably 5 to 50 times, more preferably 5 to 20 timesthe mass of a compound represented by the general formula (IX), althoughthis is not particularly limited thereto. The poor solvents may be usedsingly or in combinations of two or more. Alternatively the poor solventmay be mixed with a different solvent for use. Examples of the differentsolvent for mixing include esters such as ethyl acetate, n-butylacetate, and y-butyrolactone, ketones such as acetone, methyl ethylketone, and methyl isobutyl ketone, hydrocarbons such as benzene,toluene, xylene, and cumene, ethers such as tetrahydrofuran, diethylether, and 1,4-dioxane, alcohols such as methanol, ethanol, isopropylalcohol, and ethylene glycol monomethyl ether, dimethyl sulfoxide(DMSO), N,N-dimethylformamide (DMF), and acetonitrile, although this isnot limited thereto. In the case of using a mixture of two or moresolvents as a poor solvent, the mixing ratio is not particularlylimited.

After precipitation of solid of the compound represented by the generalformula (IX) by crystallization, the solid may be washed forpurification as needed. The solvent for use in washing is desirably thesame poor solvent as described above, although this is not particularlylimited. The amount of the washing solvent used is also not particularlylimited. The produced solid is dried under reduced pressure, so that acompound represented by the general formula (IX) can be extracted assolid. As described above, the reaction of the compound produced in the[Step 1] and [Step 2] are performed, and then the compound representedby the general formula (VI) produced in the [step 2] is stopped with anacid compound or a proton compound, so that the polyalkylene glycolderivative represented by the general formula (IX) can be obtained. Thatis to say, the present invention also relates to a method for producinga polyalkylene glycol derivative represented by the general formula(IX), the method containing the above-described steps.

Specific example of the basic compound for use in the subsequentreaction of the compound represented by the general formula (IX) withthe electrophile (I) include potassium hydroxide, sodium hydroxide, andpotassium tert-butoxide, although this is not limited thereto. Theamount of the basic compound added is, for example, 1 to 10 equivalents,preferably 1 to 5 equivalents, more preferably 1 to 2 equivalents,relative to the number of moles of the compound represented by thegeneral formula (IX).

Conditions during the reaction of the compound represented by thegeneral formula (IX) with the electrophile (I), such as reactiontemperature is the same as the conditions during the reaction of thecompound represented by the general formula (VI) with the electrophile(I) in the embodiment not through purification, as described above.Moreover, in the case of the compound represented by the general formula(II) produced through the reaction of the compound represented by thegeneral formula (IX) with the electrophile (I), the solid of thecompound represented by the general formula (II) may be extracted foruse prior to the subsequent step. However the extraction method is thesame as the method for extracting the compound represented by thegeneral formula (II) in the embodiment not through purification, asdescribed above.

In the [Step 4], deprotection of the protective groups in the compoundrepresented by the general formula (II) produced in the [Step 3] isperformed. The deprotection is performed without using a heavy metalcatalyst. The heavy metal catalyst here means a catalyst using a heavymetal such as, for example, Co, Ni, Pd, Pt, Rh, Ru, Cu, or Cr as a rawmaterial.

In the [Step 4], the method for performing deprotection without using aheavy metal catalyst is not particularly limited, however, in the casein which R_(A) ^(1a) and/or R_(A) ^(1b) in the general formula (II)represent a silyl group (electrophile (I-I)), for example, water or analcohol (R⁶OH: in the formula, R⁶ represents a hydrocarbon group having1 to 5 carbon atoms) is reacted with the compound represented by thegeneral formula (II) in the presence of an acid catalyst, so that thecompound represented by the general formula (II) may be converted to thecompound represented by the general formula (III). Specific examples ofthe acid catalyst for use include carboxylic acids such as formic acid,acetic acid, propionic acid, succinic acid, citric acid, tartaric acid,fumaric acid, malic acid, and trifluoroacetic acid, inorganic acids suchas hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, andperchloric acid, and sulfonic acids such as benzenesulfonic acid andp-toluenesulfonic acid, and solid acids such as AMBERLYST SERIES made byOrgano Corporation, although this is not limited thereto. The amount ofthe acid compound used is, for example, 0.01 to 1000 equivalents,preferably 0.1 to 100 equivalents, more preferably 1 to 10 equivalents,relative to the number of moles of the compound represented by thegeneral formula (II). The acid compounds may be used singly or incombinations of two or more. In that case, the mixing ratio is notparticularly limited.

In the case in which R_(A) ^(1a) and/or R_(A) ^(1b) represent atert-butyloxycarbonyl group (electrophile (I-II)), for example,deprotection may be performed by allowing a strong acid such astrifluoroacetic acid and hydrochloric acid to act on the compoundrepresented by the general formula (II). The amount of the strong acidused is, for example, 0.01 to 1000 equivalents, preferably 0.1 to 100equivalents, more preferably 1 to 10 equivalents, relative to the numberof moles of the compound represented by the general formula (II).

In the case in which R_(A) ^(1a) and R_(A) ^(1b) represent anN-phthaloyl group (electrophile (I-III)), for example, the phthaloylgroup may be eliminated by reacting a hydrazine hydrate with thecompound represented by the general formula (II) in an alcohol. Examplesof the alcohol for use include methanol, ethanol, n-propyl alcohol,isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, and tert-butylalcohol. The amount of the alcohol used is, for example, 1 to 100 times,preferably 3 to 50 times, more preferably 5 to 10 times the mass of thecompound represented by the general formula (II). The amount of thehydrazine hydrate used is, for example, 1 to 50 equivalents, preferably2 to 20 equivalents, more preferably 3 to 10 equivalents, relative tothe number of moles of the compound represented by the general formula(II).

In the case in which R_(A) ^(1a) and/or R_(A) ^(1b) represent a benzylgroup or an allyl group (electrophile (I-IV)), for example, deprotectionof the compound represented by the general formula (II) may be performedunder the condition of Birch reduction in which liquid ammonium andmetal sodium are used. The amount of liquid ammonium used is, forexample, 1 to 100 times, preferably 3 to 50 times, more preferably 5 to10 times the mass of the compound represented by the general formula(II). The amount of metal sodium used is, for example, 2 to 50equivalents, preferably 2 to 10 equivalents, more preferably 2 to 5equivalents, relative to the number of moles of the compound representedby the general formula (II). As in the examples above, deprotection maybe performed by appropriately selecting the condition where a heavymetal catalyst is not used, and the condition is not limited.

In the case in which deprotection is performed with an acid catalyst, aproduced amine represented by the general formula (III) and an acidforms a salt, and the acid cannot be removed in some cases. In suchcases, when a basic compound is added to the produced salt and isreacted with the acid, a salt of the added basic compound and the acidis formed, and therefore, the amine represented by the general formula(III) can be extracted. The produced salt can be removed by filtration.In the case in which the produced salt is incorporated into the polymer,the salt can be removed with an adsorption material. As the adsorptionmaterial, the adsorption materials as described in the above-mentioned[Step 3] may be used, though not particularly limited thereto. Theamount of adsorbent used is, for example, 0.01 to 10 times, preferably0.1 to 8 times, more preferably 0.3 to 6 times the mass of the compoundrepresented by the general formula (III), though not particularlylimited. Examples of the basic compound for use include potassiumhydroxide, sodium hydroxide, potassium tert-butoxide, sodium methoxide,and potassium methoxide, though not limited thereto. The amount of thebasic compound added is, for example, 1 to 10 equivalents, preferably 1to 5 equivalents, more preferably 1 to 2 equivalents, relative to thenumber of moles of the acid catalyst for use in deprotection. As asolvent for use in filtration, the reaction solvent may directly beused, or filtration may be performed after solvent substitution with asolvent in which a salt is easy to precipitate. Specific examples of thesolvent in which a salt is easy to precipitate include ethers such asTHF and 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene, andxylene, esters such as ethyl acetate, n-butyl acetate, andγ-butyrolactone, ketones such as acetone, methyl ethyl ketone, andmethyl isobutyl ketone, dimethyl sulfoxide (DMSO), N,N-dimethylformamide(DMF), and acetonitrile, though not limited thereto. The aromatichydrocarbons such as benzene, toluene, and xylene are preferred for thepurpose of enhancing the filterability. These solvents may be used aloneor in combination of two or more. In that case, the mixing ratio is notparticularly limited.

In removing the acid catalyst, the adsorption material may directly beadded to the reaction system without adding a basic compound, however,in that case, there is a possibility that the filterability is willdecrease. Therefore, the adsorption material is preferably used afterthe above-mentioned addition of the basic compound.

Crystallization may be performed with a poor solvent directly afterdeprotection, or crystallization may also be performed after solventsubstitution with a good solvent, or crystallization may also beperformed after the above-mentioned reaction with the basic compound andthe treatment with an adsorption material. Specific examples of the goodsolvent include ethers such as THF and 1,4-dioxane, aromatichydrocarbons such as benzene, toluene, and xylene, esters such as ethylacetate, n-butyl acetate, and y-butyrolactone, ketones such as acetone,methyl ethyl ketone, and methyl isobutyl ketone, dimethyl sulfoxide(DMSO), N,N-dimethylformamide (DMF), and acetonitrile, though notlimited thereto. These solvents may be used singly or in combinations oftwo or more. In that case, the mixing ratio is not particularly limited.The concentration of the compound after solvent substitution is, forexample, 10 to 50 mass %, preferably 15 to 45 mass %, more preferably 20to 40 mass %.

The poor solvent for use has a low solubility for the compoundrepresented by the general formula (III). Specific examples of thesuitable poor solvent for use include hydrocarbon such as hexane,heptane, octane, nonane, decane, cyclopentane, cyclohexane,cycloheptane, and cyclooctane, and ethers such as diethyl ether,diisopropyl ether, and di-n-butyl ether. The amount of the poor solventused is, for example, 5 to 100 times, preferably 5 to 50 times, morepreferably 5 to 20 times the mass of a compound represented by thegeneral formula (III), although this is not particularly limitedthereto. The poor solvents may be used singly or in combinations of twoor more. Alternatively the poor solvent may be mixed with a differentsolvent for use. Examples of the different solvent for mixing includeesters such as ethyl acetate, n-butyl acetate, and y-butyrolactone,ketones such as acetone, methyl ethyl ketone, and methyl isobutylketone, hydrocarbons such as benzene, toluene, xylene, and cumene,ethers such as tetrahydrofuran, diethyl ether, and 1,4-dioxane, alcoholssuch as methanol, ethanol, isopropyl alcohol, and ethylene glycolmonomethyl ether, dimethyl sulfoxide (DMSO), N,N-dimethylformamide(DMF), and acetonitrile, though not limited thereto. In the case ofusing a mixture of two or more solvents as a poor solvent, the mixingratio is not particularly limited.

In the [Step 4], after precipitation of solid of the compoundrepresented by the general formula (III) by crystallization, the solidmay be washed for purification as needed. The solvent for use in washingis desirably the same poor solvent as described above, although this isnot particularly limited. The amount of the washing solvent used is alsonot particularly limited. The produced solid is dried under reducedpressure, so that the compound represented by the general formula (III)can be extracted as solid.

In the present invention, the amino group is obtained by thedeprotection as described above. Thus, by-products (compoundsrepresented by the following (VII) to (IX)) that may be produced by, forexample, a method described in Japanese Patent No. 3562000 are notsubstantially produced, and a narrowly distributed and high-puritypolyalkylene glycol derivative having an amino group at an end, thepolyalkylene glycol derivative represented by the general formula (III),may finally be synthesized. In contrast, in the case in which acyanoethylated compound is subjected to hydrogen reduction to lead to apolyalkylene glycol derivative having an amino group by, for example, amethod described in Japanese Patent No. 3562000, the hydrogen reductionis accompanied by β-elimination of acrylonitrile, and therefore,by-production of a PEG derivative represented by the following generalformula (IX) and a polyacrylonitrile cannot be prevented. Moreover,there is a possibility that a secondary and tertiary amine compoundsrepresented by the following general formula (VII) and (VIII) areproduced in the hydrogen reduction process due to addition of an amineas a product to an imine as a reduction intermediate of nitrile in theconventional method. The side reactions may be suppressed by addingammonia or acetic acid to the reaction system; however, it is difficultto completely control the side reactions by a conventional method.

HNR_(A)—(OR_(A) ⁴)_(n)—OR_(A) ³)₂  (VII)

NR_(A) ²—(OR_(A) ⁴)_(n)—OR_(A) ³)₃  (VIII)

H—(OR_(A) ⁴)_(n)—OR_(A) ³  (IX)

(In the general formulas (VII) to (IX), R_(A) ², R_(A) ³, R_(A) ⁴, and nare the same as R_(A) ², R_(A) ³, R_(A) ⁴, and n in the general formulas(I) to (III))

The following [Step 5] to [Step 8] after the [Step 4] are optionalpurifying steps. In the case in which a protective group in the compoundrepresented by the general formula (II) produced in the [Step 3] is aprotective group that is deprotectable with an acid, deprotection may beperformed in parallel by performing the [Step 5] to the [Step 8] afterthe [Step 3], so that the process can be further simplified. That is tosay, in this case, the [Step 4] (the step of obtaining the compoundrepresented by the general formula (III) by deprotecting the compoundrepresented by the general formula (II)) may be performed specificallyby the operation in the [Step 5] to the [Step 8]. Moreover, freezedrying is not necessary in the [Step 5] to [Step 8] as will be describedbelow in purifying and extracting the compound represented by thegeneral formula (III). Therefore, the method including the [Step 5] to[Step 8] has an advantage that simplification of facilities andprocesses can be realized in producing a polyalkylene glycol derivativeon an industrial scale.

In the [Step 5], the reaction products produced in the [Step 3] or the[Step 4] are reacted with a strong acid cation exchange resin, and thenthe strong acid cation exchange resin is washed with water or monohydricalcohol having 1 to 5 carbon atoms for separation of substances otherthan the compound represented by the general formula (III).

Specific examples of the strong acid cation exchange resin for use inthe [Step 5] include AMBERLITE series (IR120B, IR124B, 200CT, and 252)made by Organo Corporation, AMBERJET series (1020, 1024, 1060, and 1220)made by Organo Corporation, DIAION series (e.g. SK104, SK1B, SK110,SK112, PK208, PK212, PK216, PK218, PK220, PK228, UBKO8, UBK10, UBK12,UBK510 L, UBK530, and UBK550) made by Mitsubishi Chemical Corporation,DOWEX series (50W×2 50-100, 50W×2 100-200, 50W×4 100-200, 50W×8 50-100,50W×8 100-200, 50W×8 200-400, HCR-S, and HCR-W2(H)) made by Dow ChemicalCo., although this is not limited thereto. The amount of the strong acidcation exchange resin used is, for example, 1 to 50 times, preferably 1to 30 times, more preferably 1 to 20 times the mass of the compoundrepresented by the general formula (III).

In the case of using a strong acid cation exchange resin, the strongacid cation exchange resin may be treated with an acid compound prior touse. Since commercially available strong acid cation exchange resins areoften in an alkali metal sulfonate salt state, the pretreatment with anacid compound regenerates sulfo groups, so that the reaction efficiencycan be improved. In this case, examples of the acid compound for useinclude inorganic acids such as hydrochloric acid, sulfuric acid, nitricacid, phosphoric acid, and perchloric acid, although this is not limitedthereto. The amount of the acid compound used is, for example, 1 to 15times, preferably 1 to 10 times, more preferably 1 to 8 times the massof the strong acid cation exchange resin. After treatment of the strongacid cation exchange resin with an acid compound, the acid compound isseparated from the resin by water washing, and water is separated by awater-soluble organic solvent such as methanol and ethanol as needed.

Examples of the method for reacting the reaction products obtained inthe [Step 3] or the [Step 4] with a strong acid cation exchange resininclude: flowing the solution of the products in a column filled withthe ion exchange resin to cause adsorption; and circulating the solutionof crude products between a cartridge filled with the resin and thereaction tank for the [Step 3] or the [Step 4]; although this is notparticularly limited. In the case in which the [Step 5] is performedafter the [Step 3] directly, the compound represented by the generalformula (II) is reacted with water or alcohol (R³OH: in the formula, R³represents a hydrocarbon group having 1 to 5 carbon atoms) in thepresence of a catalyst of the strong acid cation exchange resin, so thatthe compound represented by the general formula (III) may be adsorbed bythe strong acid cation exchange resin after deprotection.

The strong acid cation exchange resin with the adsorbed compoundrepresented by the general formula (III) is then washed with water or amonohydric alcohol having 1 to 5 carbon atoms, so that compounds otherthan the target substance can be separated. Examples of the monohydricalcohol having 1 to 5 carbon atoms include methanol, ethanol, n-propylalcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol,tert-butyl alcohol, n-pentyl alcohol, isopentyl alcohol, and neopentylalcohol. In performing washing, water or a monohydric alcohol may beused singly, or a mixture of water and one or more alcohols or a mixtureof two or more alcohols may be used. In that case, the mixing ratio isnot particularly limited. The amount of water or a monohydric alcoholhaving 1 to 5 carbon atoms or a mixture thereof used is, for example, 1to 30 times, preferably 1 to 20 times, more preferably 1 to 10 times themass of the strong acid cation exchange resin for use, although this isnot particularly limited.

In the [Step 6], the strong acid cation exchange resin with the adsorbedcompound represented by the general formula (III) is reacted with abasic compound in water or a monohydric alcohol having 1 to 5 carbonatoms, so that a compound represented by the general formula (III) isextracted in water or the monohydric alcohol. In performing thereaction, water or the monohydric alcohol may be used singly, or amixture of water and one or more alcohols or a mixture of two or morealcohols may be used. In that case, the mixing ratio is not particularlylimited. Examples of the method for reacting a strong acid cationexchange resin and a basic compound include: flowing the solution ofbasic compound in a column filled with the ion exchange resin to causereaction; and circulating the solution of the basic compound between acartridge filled with the ion exchange resin and the reaction tank forthe [Step 3], the [Step 4] and the [Step 5]; as described in the [Step5], although this is not particularly limited.

Specific examples of the monohydric alcohol for use in the [Step 6]include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butylalcohol, sec-butyl alcohol, tert-butyl alcohol, n-pentyl alcohol,isopentyl alcohol, and neopentyl alcohol. The amount of water or amonohydric alcohol used is, for example, 1 to 30 times, preferably 1 to20 times, more preferably 1 to 10 times the mass of the strong acidcation exchange resin for use, although this is not particularlylimited.

As the basic compound for use in the [Step 6], ammonia dissolved inwater or an organic solvent (e.g. ammonia water and methanol solution ofammonia) may be suitably used, and primary, secondary and tertiaryaliphatic amines, mixed amines, aromatic amines, and heterocyclic aminesmay be also used. Examples of the primary aliphatic amines includemethylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine,isobutylamine, sec-butylamine, tert-butylamine, and ethylene diamine;examples of the secondary aliphatic amines include dimethylamine,diethylamine, di-n-propylamine, diisopropylamine, di-n-butylamine,diisobutylamine, di-sec-butylamine; examples of the tertiary aliphaticamines include trimethylamine, triethylamine, tri-n-propylamine,triisopropylamine, tri-n-butylamine, tri-isobutylamine, andtri-sec-butylamine; examples of the mixed amines includedimethylethylamine, methylethylpropylamine, benzylamine, phenethylamine,benzyldimethylamine; specific examples of the aromatic amines and theheterocyclic amines include aniline derivatives (e.g. aniline,N-methylaniline, N-ethylaniline, N-propylaniline, N,N-dimethylaniline,2-methylaniline, 3-methylaniline, 4-methylaniline, ethylaniline,propylaniline, trimethylaniline, 2-nitroaniline, 3-nitroaniline,4-nitroaniline, 2,4-dinitroaniline, 2,6-dinitroaniline,3,5-dinitroaniline, and N,N-dimethyltoluidine), diphenyl(p-tolyl)amine,methyldiphenylamine, triphenylamine, phenylenediamine, naphthylamine,diaminonaphthalene, and pyridine derivatives (e.g. pyridine,methylpyridine, ethylpyridine, propylpyridine, butylpyridine,4-(1-butylpentyl)pyridine, dimethylpyridine, trimethylpyridine,triethylpyridine, phenylpyridine, 3-methyl-2-phenylpyridine,4-tert-butylpyridine, diphenylpyridine, benzylpyridine, methoxypyridine,butoxypyridine, dimethoxypyridine, 4-pyrrolidinopyridine,2-(1-ethylpropyl)pyridine, aminopyridine, and dimethylaminopyridine),although this is not limited thereto. Alternatively an alkali aqueoussolution such as potassium hydroxide and sodium hydroxide may be used asa basic compound. The amount of the basic compound used is, for example,0.1 to 100 times, preferably 0.1 to 10 times, more preferably 0.1 to 5times the mass of the strong acid cation exchange resin for use.

In the [Step 7], after concentration of the reaction liquid in the [Step6], the solvent is substituted with a good solvent for a compoundrepresented by the general formula (III) contained in the reactionliquid, such that the concentration of the compound represented by thegeneral formula (III) is adjusted to be 10 to 50 mass %.

Examples of the good solvent for the compound represented by the generalformula (III) for use in the [Step 7] include THF and the same goodsolvents as exemplified in the [Step 3], although this is not limitedthereto. The good solvents may be used singly or in combinations of twoor more. In that case, the mixing ratio is not particularly limited.After solvent substitution, the concentration of the compound is, forexample, 10 to 50 mass %, preferably 15 to 45 mass %, more preferably 20to 40 mass %.

In the [Step 8], the solution produced by concentration in the [Step 7]is dripped into a poor solvent for the compound represented by thegeneral formula (III) to be precipitated. The compound represented bythe general formula (III) is thereby produced.

The poor solvent for use in the [Step 8] has a low solubility for thecompound represented by the general formula (III). Specific examples ofthe poor solvent include the same poor solvent as exemplified in the[Step 3] as described above, although this is not limited thereto. Theamount of the poor solvent used is, for example, 5 to 100 times,preferably 5 to 50 times, more preferably 5 to 20 times the mass of thecompound represented by the general formula (III), although this is notparticularly limited. The poor solvent may be used singly, andalternatively the poor solvent may be mixed with a different solvent foruse. Examples of the different solvent for mixing include the samedifferent solvent as exemplified in the [Step 3] as described above,though not limited thereto. Moreover, in the case of mixing with adifferent solvent for use, the mixing ratio is not particularly limited.

In the [Step 8], after precipitation of solid by crystallization, thesolid may be washed for purification as needed. Preferably the solventfor use in washing is the same poor solvent as described above, althoughthis is not particularly limited. The amount of the washing solvent usedis also not particularly limited. The produced solid is dried underreduced pressure, so that a compound represented by the general formula(III) can be extracted as solid.

In addition, in the case in which the compound represented by thegeneral formula (III) is extracted as an aqueous solution in theoperation after the [Step 6] (in the [Step 6] to [Step 8]), the compoundrepresented by the general formula (III) may be extracted by freezedrying the aqueous solution. However, in this case, special facilitiesare required for freeze drying and a long time is required for completeremoval of water, so that an industrial-scale production is difficult insome cases. In the present invention, however, the purificationpreferably using an organic solvent as described above allows forsimplified facilities and processes.

Regarding the compound represented by the general formula (III) obtainedafter performing the [Step 1] to [Step 4] of the present invention, orobtained after performing the [Step 5] to [Step 8] subsequent to the[Step 1] to [Step 4] or the [Step 1] to [Step 3] of the presentinvention, a narrowly distributed polymer can be obtained because theinitiation reaction is sufficiently faster than the propagation reactionduring polymerization, the amount of water mixed as a factor oftermination reaction is small, and further, the polymerization initiatoris uniformly dissolved in the polymerization solvent.

That is to say, the compound represented by the general formula (III)produced by the production method of the present invention is narrowlydistributed, and the dispersity (weight average molecular weight(Mw)/number average molecular weight (Mn)) is, for example, 1.0 to 1.20,preferably 1.0 to 1.10, more preferably 1.0 to 1.06. Moreover, themolecular weight of the compound represented by the general formula(III) produced by the production method of the present invention ispreferably 5,000 to 25,000, more preferably 8,000 to 15,000 as theweight average molecular weight (Mw). The molecular weight anddispersity of a polymer in the present Description are defined as valuesobtained in the case in which measurement is performed with gelpermeation chromatography (hereinafter, alleviated as “GPC”).

The amount of by-products (VII) and (VIII) (compound represented by thegeneral formula (VII) and compound represented by the general formula(VIII)) mixed in the product obtained after performing the [Step 1] to[Step 4], or in the product obtained after performing the [Step 5] to[Step 8] subsequent to the [Step 1] to [Step 4] or the [Step 1] to [Step3] is preferably 3% or less, more preferably 1% or less expressed by anarea content ratio (%) measured by GPC, relative to the total area ofthe compounds represented by the general formula (III), (VII), and(VIII). Most preferably, the obtained product does not contain any oneof the compounds represented by the general formula (VII) and thecompound represented by the general formula (VIII). According to thepresent embodiment, any one of the compounds represented by the generalformula (VII) and the compounds represented by the general formula(VIII) are not actually produced.

The amount of by-product (IX) (compound represented by the generalformula (IX)) mixed in the product obtained after performing the [Step1] to [Step 4], or in the product obtained after performing the [Step 5]to [Step 8] subsequent to the [Step 1] to [Step 4] or the [Step 1] to[Step 3] is preferably 2 mol % or less, more preferably 1 mol % or lessexpressed by a content ratio in terms of composition ratio (mol %)measured by proton nuclear magnetic resonance (1H-NMR), relative to thetotal amount of substances of the compound represented by the generalformula (III) and the compound represented by the general formula (IX).Most preferably, the obtained product does not contain a compoundrepresented by the general formula (IX). According to the presentembodiment, a compound represented by the general formula (IX) is notactually produced.

Moreover, the product obtained after performing the [Step 1] to [Step4], or the product obtained after performing the [Step 5] to [Step 8]subsequent to the [Step 1] to [Step 4] or the [Step 1] to [Step 3] doesnot substantially contain such by-products (compounds represented by thegeneral formulas (VII) to (IX) as described above. Preferably,X_(A)/(X_(A)+X_(B)) is 0.95 or more, where X_(A) represent the totalamount of the main product (compound represented by the general formula(III)), X_(B) represent the total amount of by-products, and both X_(A)and X_(B) are converted from the measurement results by GPC and 1H-NMR.Most preferably, the obtained product does not contain such by-productsas described above.

The content of heavy metal impurities measured by a high frequencyinductively coupled plasma mass spectrometer (ICP-MS) in the productobtained after performing the [Step 1] to [Step 4], or in the productobtained after performing the [Step 5] to [Step 8] subsequent to the[Step 1] to [Step 4] or the [Step 1] to [Step 3] is preferably 100 ppbor less, more preferably 10 ppb or less. The measurement of the amountof heavy metal impurities in a product is generally performed with theabove-described ICP-MS, however the measurement method is not limitedthereto. When analyzed with an ICP-MS, a polymer sample is diluted witha solvent for measurement. It is essential that a solvent used dissolvethe polymer and not contain a metal. Ultrapure water andN-methyl-2-pyrrolidone for electronic industry are particularlypreferred for the solvent; however, the solvent is not limited thereto.The dilution ratio is preferably 10 to 100,000 times, more preferably 50to 1,000 times, though not limited thereto.

As described above, it is known that heavy metals, when accumulated invivo, have adverse effects. In the conventional synthesis methodsdescribed in, for example, Japanese Patent No. 3050228 and JapanesePatent No. 3562000, a cyano group is converted to an aminomethyl groupwith a Raney nickel catalyst, there is concern that a heavy metal may bemixed in a product. According to “ICH Q3D: GUIDELINES FOR ELEMENTALIMPURITIES Draft ICH consensus Guideline” reported in InternationalConference on Harmonization of Technical Requirements for Registrationof Pharmaceuticals for Human Use, as elementary impurities that needrisk assessment among elementary impurities, As, Pb, Cd, and Hg arelisted in Class 1, V, Mo, Se, and Co are listed in Class 2A, Ag, Au, Tl,Pd, Pt, Ir, Os, Rh, and Ru are listed in Class 2B, and Sb, Ba, Li, Cr,Cu, Sn, and Ni are listed in Class 3. In the above conventional method,examples of the heavy metal for use in hydrogen reduction include Co,Ni, Pd, Pt, Rh, Ru, Cu, and Cr; however, these metals are listed as themetals that need risk assessment, and reducing the mixing amount thereofwill be required more and more in the future.

In contrast, since the method of the present invention does not requirethe use of a heavy metal catalyst, there is no risk that a heavy metalwill be mixed in a product. As a result thereof, the method of thepresent invention is a production method that is particularly suitablefor obtaining a compound represented by the general formula (III) foruse in medical supplies.

EXAMPLES

The present invention is specifically illustrated with reference to thefollowing Examples and Comparative Examples, though the presentinvention is not limited to the following Examples. In the notation ofmolecular weight in Examples, the weight average molecular weight (Mw)and the number average molecular weight (Mn) are values in terms ofpolyethylene glycol measured by GPC. Measurement by GPC was performedunder the following conditions:

Column: TSK gel Super AWM-H, Super AW-3000

Developing solvent: DMF (0.01 mol/L lithium bromide solution)

Column oven temperature: 60° C.

Sample concentration: 0.20 wt. %

Sample injection volume: 25 μl

Flow rate: 0.3 ml/min

[Synthesis Example 1] Synthesis of Polymerization Initiator (Va)

After placement of a stirring bar in a 500 mL two neck round-bottomflask, a rectification tube, a thermometer, a Liebig condenser, afractionating column, two 50 mL round-bottom flasks, and one 300 mL twoneck flask were connected, so that a distillation device was assembled.After the degree of vacuum in the device was held at 10 Pa or less, theinternal part of the device was heated with an oil bath and a heat gun,so that the water content in the system was removed. Subsequentlydiethylene glycol monomethyl ether (made by Tokyo Chemical Industry Co.,Ltd.) was injected into the 500 mL two neck round-bottom flask undernitrogen stream, and reduced-pressure distillation was performed. Themeasured water content ratio was 1 ppm or less after distillation(Measurement of the water content ratio was performed by a Karl Fishermoisture meter, and the same applies hereinafter).

After placement of a stirring bar in a 3 L two neck round-bottom flask,a rectification tube, a thermometer, a Dimroth condenser, afractionating column, a 200 mL round-bottom flask, and a 2 L two neckflask were connected, so that a distillation device was assembled. Afterthe degree of vacuum in the device was held at 10 Pa or less, theinternal part of the device was heated with an oil bath and a heat gun,so that the water content in the system was removed. Subsequentlydehydrated THF (made by Kanto Chemical Co., Ltd.), metal sodium pieces(made by Kanto Chemical Co., Ltd.), and benzophenone (made by TokyoChemical Industry Co., Ltd.) were injected into the 3 L two neckround-bottom flask under nitrogen stream, and refluxing was performedunder normal pressure for 5 hours. After confirmation that the color inthe 3 L two neck round-bottom flask changed into bluish purple, thedistilled THF was extracted into the 2 L two neck flask. The measuredwater content ratio was 1 ppm or less after distillation.

In a glove box under nitrogen atmosphere, 15.98 g of potassium hydride(in a mineral oil form, made by Kanto Chemical Co., Ltd.) was weighedand fed into a 500 mL four neck flask connected to a thermometer, adripping funnel, and a Dimroth condenser under nitrogen stream. Afterthe mineral oil was washed with hexane to be separated, vacuum dryingwas performed for about two hours to obtain 6.193 g (154 mmol) ofpotassium hydride. Into the flask, 127.65 g of distilled THF was addedwith a syringe. Into the dripping funnel, 18.737 g (156 mmol) ofdistilled diethylene glycol monomethyl ether was injected to be drippedslowly. Maturation was performed for 2 hours, so that 148.62 g (1.05mmol/g) of a THF solution of the polymerization initiator (Va) wasproduced. Precipitation of a salt and cloudiness were not observed atthat time ((Va) mass/THF solution mass=16.6 wt. %). The ratio of theamounts of substances between the polymerization initiator (Va)synthesized by the above-described reaction and the alcohol that is aninitiator raw material is 99:1 (mol %).

A reaction scheme is shown in the following.

[Synthesis Example 1-1] Synthesis of Polymerization Initiator (Va) byAnother Method

Distillation of diethylene glycol monomethyl ether and THF was performedin the same manner as in the [Synthesis Example 1].

In a glove box under nitrogen atmosphere, 1.28 g of naphthalene and 0.43g of potassium were weighed and fed into a 100 mL three neck flask, andvacuum drying was performed for 1 hour. The flask was then brought backunder a nitrogen atmosphere, and 13.58 g of distilled THF was added intothe flask with a syringe. Stirring was performed for 1 hour to prepare aTHF solution of potassium naphthalenide (0.65 mmol/g). On the otherhand, 1.00 g of distilled diethylene glycol monomethyl ether was weighedwith a syringe and fed into a 50 mL three neck flask under nitrogenatmosphere. 12.33 g of the THF solution of potassium naphthalenideprepared above was dripped thereto at normal temperature. Maturation wasperformed for 1 hour, so that 13.33 g (0.64 mmol/g) of a THF solution ofthe polymerization initiator (Va) was produced. Precipitation of a saltand cloudiness were not observed at that time ((Va) mass/THF solutionmass=9.9 wt. %). The ratio of the amounts of substances between thepolymerization initiator (Va) synthesized by the above-describedreaction and the alcohol that is an initiator raw material is 96:4 (mol%). A reaction scheme is shown in the following.

[Synthesis Example 2] Synthesis of Electrophile (Ia) (2-1) Synthesis ofSilyl Protector (I-1)

In a 300 ml three neck flask, 6.0 g of 3-amino-1-propanol, 28.74 g oftriethylamine, and 18.0 g of toluene were charged, and then 75.0 g ofTESOTf was dripped therein under a nitrogen atmosphere. Stirring wasthen performed at 80° C. for 25 hours. The reaction liquid wastransferred into a separatory funnel, the lower layer was separated, andthe upper layer was distilled under reduced pressure, so that 31.47 g(yield rate 93.3%) of a silyl protector (I-1) was produced.

Silyl protector (I-1)

Colorless liquid

Boiling point 133 to 138° C./10 Pa

¹H-NMR (500 MHz, CDCL3): δ=0.60 (18H, q), 0.94 (27H, t), 1.62 (2H, m),2.83 (2H, m), and 3.54 (2H, t)

In the formula, TES means a triethylsilyl group.

(2-2) Synthesis of Alcohol Having Silyl-Protected Amino Group (1-2)

In a 200 ml one neck flask, 30.98 g of silyl protector (I-1), 30.98 g ofmethanol, and 0.2 g of sodium methoxide were charged, and stirring wasperformed at 60° C. for 18 hours. Triethylmethoxy silane was thendistilled under reduced pressure, 30.98 g of methanol was again placedinto the flask, and stirring was performed at 60° C. The same operationwas repeated, then quenching was performed with sodium bicarbonate aftercompletion of reaction, then solvent substitution with toluene wasperformed, and a salt was then removed by filtration. Toluene was thendistilled away under reduced pressure, so that 22.66 g (crude yield rate96.4%) of an alcohol having a silyl-protected amino group (1-2) wasproduced. The crude product had a sufficient purity as an intermediate,and was used directly for the subsequent step.

Alcohol having a silyl-protected amino group (1-2)

Colorless liquid

¹H-NMR (500 MHz, CDCL3): δ=0.60 (12H, q), 0.93 (18H, t), 1.67 (2H, m),2.85 (2H, m), and 3.59 (2H, m)

(2-3) Synthesis of Electrophile (Ia)

In a 50 ml three neck flask, 14.7 g of TsCl, 5 g of methylene chloride,and 5.0 g of triethylamine were charged, and a solution of 5.0 g of thealcohol having a silyl-protected amino group (1-2) dissolved in 10.0 gof methylene chloride was dripped therein while the flask wasice-cooled. The temperature was brought back to normal temperature,stirring was performed for 13 hours, then quenching was performed withwater, and then extraction was performed with toluene. The toluenesolution was then concentrated, so that 7.6 g (crude yield rate 100%) ofan electrophile (Ia) was produced. The crude product had a sufficientpurity as an intermediate, and was used directly for the subsequentstep.

Electrophile (Ia)

Brown liquid

¹H-NMR (500 MHz, CDCL₃): δ=0.54 (12H, q), 0.89 (18H, t), 1.68 (2H, m),2.45 (3H, s), 2.71 (2H, m), and 3.98 (2H, t)

[Synthesis Example 3] Synthesis of Electrophile (Ib)

In a 200 ml three neck flask, 15.93 g of 3-bromopropylaminehydrobromate, 27.26 g of triethylamine, and 47.79 g of toluene werecharged, and 50.00 g of TESOTf was then dripped therein under nitrogenatmosphere. Stirring was then performed at 80° C. for 63 hours. Thereaction solution was transferred to a separatory flask, the lower layerwas separated, and the upper layer was distilled under reduced pressure,so that 8.00 g (yield rate 30.0%) of an electrophile (Ib) was produced.

Electrophile (Ib)

Colorless liquid

Boiling point 108° C./30 Pa

¹H-NMR (500 MHz, CDCL₃): δ=0.61 (12H, q), 0.94 (18H, t), 1.92 (2H, m),2.90 (2H, m), and 3.31 (2H, t)

[Synthesis Example 4] Synthesis of Electrophiles (Ic) to (Ii)

The following electrophiles (Ic) to (Ii) were synthesized in the samemanner as in the [Synthesis Example 3], except that TESOTf was changedto corresponding protecting agents.

In the general formulas, “TMS” means trimethyl silyl, “TBS” meanstert-butyl dimethylsilyl, and “Boc” means tert-butoxycarbonyl.

[Polymer Synthesis Example 1] Synthesis of Polymer (VIa)

A stirring bar was placed in a 2 L four neck flask connected to athermometer, a dripping funnel, and a Dimroth condenser. After thedegree of vacuum in the device was held at 10 Pa or less, the internalpart of the device was heated with an oil bath and a heat gun, so thatthe water content in the system was removed. Subsequently, 4.96 g (1.05mmol/g) of the THF solution of the polymerization initiator (Va)produced in the above-described [Synthesis Example 1] and 420 g ofdistilled THF were added into the 2 L four neck flask under a nitrogenstream.

Into the dripping funnel, 60 g of ethylene oxide and 120 g of distilledTHF were injected, to be dripped into the 2 L four neck flask little bylittle. After confirming stabilization of the temperature in the 2 Lfour neck flask, the 2 L four neck flask was immersed in an oil bathheld at a temperature of 45° C. for maturation for 8 hours. Aftercompletion of the reaction, the oil bath was detached and the reactionsystem was cooled to room temperature. A reaction scheme is shown in thefollowing.

A small amount of the produced reaction system was sampled and quenchedwith acetic acid for measurement by GPC. The following results wereobtained: Mw=8,500 and Mw/Mn=1.04.

[Polymer Synthesis Example 1-1] Synthesis of Polymer (IXa)

A 2 L high pressure gas reaction vessel was dried by nitrogen purge, and8.30 g (1.05 mmol/g, 8.72 mmol) of the THF solution of thepolymerization initiator (Va) produced in the above-described [SynthesisExample 1] and 1008 g of distilled THP were added thereto under anitrogen atmosphere. After the temperature in the reaction vessel wasraised to 45° C., 112 g of ethylene oxide was continuously pressed intothe reaction vessel, and the pressure in the system was then adjusted to0.15 MPa by nitrogen pressurization. Stirring was performed at 45° C. togradually lower the pressure of the system, and after 6 hours, thepressure of the system became stable at 0.11 MPa where the reaction wasdetermined to be completed. Subsequently, the reaction was stopped with0.32 g of H₂O, then adsorption treatment was performed by adding 10 g ofKW-2000 (Kyowa Chemical Industry Co., Ltd.) and stirring the resultingmixture for 2 hours, and then KW-2000 was removed by filtration. Thereaction solution was concentrated to 448 g, 1120 g of hexane was thenplaced in a 3 L beaker with a stirring bar therein, and after drippingthe produced reaction liquid with a dripping funnel for 10 minutes,maturation was performed for 10 minutes. The produced white powder wasfiltered and then returned to the original beaker, to be washed with 560g of hexane for 10 minutes, and the produced white powder wasvacuum-dried to obtain 107 g of a polymer (IXa). The following GPCmeasurement results were obtained: Mw=12500 and Mw/Mn=1.02. A reactionscheme is shown in the following.

[Polymer Synthesis Example 2] Synthesis of Polymer (IIa)

Into a 100 ml dried three neck flask, 26 g (2.6 g in terms of solidcontent) of the THF solution of the polymer (VIa) produced in the[Polymer Synthesis Example 1] was fractionated with a syringe. Under anitrogen stream, 0.298 g of the electrophile (Ia) and 0.43 ml of a THFsolution (1 mol/L) of potassium tert-butoxide were added, and with thetemperature in the flask being held at 40° C., maturation was performedfor 5 hours. After completion of the reaction, filtration was performedwhile holding the temperature at 40° C., and a precipitated salt wasremoved. In a 200 mL beaker with a stirring bar therein, 26 g of hexanewas placed, and after dripping the produced reaction liquid with adripping funnel for 5 minutes, maturation was performed for 10 minutes.The produced white powder was filtered and then returned to the originalbeaker, to be washed with 13 g of hexane for 10 minutes. The samewashing operation was further performed once.

The produced white powder was vacuum-dried to obtain 2.30 g of a polymer(IIa). The following GPC measurement results were obtained: Mw=8800 andMw/Mn=1.04. A reaction scheme is shown in the following.

The reaction of the polymer (VIa) with an electrophile was subsequentlyperformed without purifying the polymer (VIa), and therefore it isrevealed that the present synthesis example has a substantiallysimplified process.

[Polymer Synthesis Example 2-1] Synthesis of Polymer (IIa)

A 2 L high pressure gas reaction vessel was dried by nitrogen purge, and8.30 g (1.05 mmol/g, 8.72 mmol) of the THF solution of thepolymerization initiator (Va) produced in the above-described [SynthesisExample 1] and 1008 g of distilled THP were added thereto under anitrogen atmosphere. After the temperature in the reaction vessel wasraised to 45° C., 112 g of ethylene oxide was continuously pressed intothe reaction vessel, and the pressure in the system was then adjusted to0.15 MPa by nitrogen pressurization. Stirring was performed at 45° C. togradually lower the pressure of the system, and after 6 hours, thepressure of the system became stable at 0.11 MPa where the reaction wasdetermined to be completed. After the reaction system was cooled to 40°C., 8.14 g of the electrophile (Ia) was dissolved in 81.4 g of THF, andthe resultant mixture was pressed into the system, and, further, 8.9 mlof a THF solution (1 mol/L) of potassium tert-butoxide was diluted with50 g of THF, and the resultant solution was pressed into the system.Subsequently, with the temperature being held at 40° C., maturation wasperformed for 5 hours. A precipitated salt was separated by filtration,and 11 g of an adsorption material KW-2000 was added to the filtrate,stirring was performed for 2 hours, and the adsorption material was thenremoved by filtration. The reaction solution was concentrated to 448 g.1120 g of hexane was then placed in a 3 L beaker with a stirring bartherein, and after dripping the produced reaction solution with adripping funnel for 10 minutes, maturation was performed for 10 minutes.The produced white powder was filtered and then returned to the originalbeaker, to be washed with 560 g of hexane for 10 minutes, and after thesame washing was repeated once again, the produced white powder wasvacuum-dried to obtain 109 g of a polymer (IIa). The following GPCmeasurement results were obtained: Mw=12900 and Mw/Mn=1.02. A reactionscheme is shown in the following.

It is revealed that the polymerization with ethylene oxidestoichiometrically progresses in the Polymer Synthesis Example 1-1 andthe Polymer Synthesis Example 2-1 as shown in Table 1 below.

TABLE 1 Theoretical Mw/ Yield Mw Mw Mn rate (%) Polymer Synthesis 13,00012,500 1.02 94.4 Example 1-1 Polymer Synthesis 13,300 12,900 1.02 94.1Example 2-1

[Polymer Synthesis Example 3] Synthesis of Polymer (IIIa)

Into a 50 ml three neck flask, 10 g of the Polymer (IIa) produced in the[Polymer Synthesis Example 2], 9.0 g of THF and 0.4 ml of 1N HCl aq.were fed, and stirring was performed at 40° C. for 4 hours. The reactionwas then stopped with 0.2 ml of 25 wt. % NaOH aq. After the reactionsolution was concentrated to evaporate water, a polymer solution wasprepared with 5.7 g of THF, and a precipitated salt was filtered. In a100 mL beaker with a stirring bar therein, 10 g of hexane was placed,and after dripping the produced reaction solution, maturation wasperformed for 10 minutes. The produced white powder was filtered andthen returned to the original beaker, to be washed with 5 g of hexanefor 10 minutes. The same washing operation was further performed once.

The produced white powder was vacuum-dried to obtain 0.7 g of a polymer(IIIa). The following GPC measurement results were obtained: Mw=8500 andMw/Mn=1.05. A reaction scheme is shown in the following.

Deprotection may subsequently be performed by adding hydrochloric acidwithout purifying the polymer (IIa) after the reaction in the [PolymerSynthesis Example 2], and in that case, the process was able to befurther simplified.

[Polymer Synthesis Example 3-1] Synthesis of Polymer (IIIa)

Into a 1 L three neck flask, 100 g of the polymer (IIa) produced in the[Polymer Synthesis Example 2-1], 400 g of MeOH, and 5.00 g of aceticacid were fed, and stirring was performed at 35° C. for 3 hours. Thereaction was then stopped with 24.12 g of a 28% solution of sodiummethylate in methanol. The reaction solution was concentrated, andsolvent substitution with toluene was performed, so that 450 g of apolymer solution was prepared, and a precipitated salt was filtered. Tothe produced polymer solution, 100 g of the adsorption material KW-2000was added, and treatment was performed at 35° C. for 1 hour to removetrace amount of the salt. In a 3 L beaker with a stirring bar therein,1000 g of hexane and 500 g of ethyl acetate were placed, and afterdripping the produced reaction solution, maturation was performed for 10minutes. The produced white powder was filtered and then returned to theoriginal beaker, to be washed with 600 g of hexane and 300 g of ethylacetate for 10 minutes, and the same washing operation was furtherperformed once.

The produced white powder was vacuum-dried to obtain 90 g of a polymer(IIIa). The following GPC measurement results were obtained: Mw=13,000and Mw/Mn=1.02. A reaction scheme is shown in the following.

[Polymer Synthesis Example 4] Purification of Polymer (IIIa)

The inside of a cartridge filled with 50 g of a cation exchange resinDIAION PK-208 (made by Mitsubishi Chemical Corporation) was washed with300 g of 1N hydrochloric acid, and then washed 3 times with 300 g ofion-exchanged water, and subsequently once with 300 g of methanol. Intoa 500 mL two neck flask, a 5 wt. % solution of the polymer (IIIa)obtained in the [Polymer Synthesis Example 3] in methanol (polymercontent; 10 g) was injected, and transferred into the cartridge with apump. The methanol solution discharged from the liquid outlet of thecartridge was added into the original 500 mL round-bottom flask. Theoperation was continuously performed for 2 hours, so that the polymer(IIIa) was adsorbed to the cation exchange resin. Subsequently the resinin the cartridge was washed with 300 g of methanol once, and then thepolymer (IIIa-2) was eluted from the cation exchange resin with 50 g of7N ammonia solution (methanol solution made by Kanto Chemical Co.,Ltd.). The purified polymer after the process of elution from the cationexchange resin is denoted as (“IIIa-2”).

Even when the polymer (IIa) is used directly in place of the polymer(IIIa), deprotection progresses in the methanol solution in the presenceof the cation exchange resin catalyst, and therefore both deprotectionand purification may be performed in parallel, and the process was ableto be further simplified.

The produced eluent was transferred into a 500 mL round-bottom flask,and ammonia and methanol were distilled away with a rotary evaporator.Through vacuum concentration almost to dryness, the solvent wassubstituted with toluene such that the solid content concentration ofthe polymer (IIIa-2) was adjusted to 25 wt. %.

In a 500 mL beaker with a stirring bar therein, 100 g of hexane and 50 gof ethyl acetate were mixed. After dripping of a 25 wt. % producedpolymer (IIIa-2) solution for 10 minutes with a dripping funnel,stirring was performed for 20 minutes, and maturation was performed. Theproduced white powder was filtered and then returned to the originalbeaker, to be washed with a mixed solvent of 50 g of hexane and 25 g ofethyl acetate for 20 minutes. The same washing operation was furtherperformed once.

The produced white powder was vacuum-dried to obtain 8.51 g of a polymer(IIIa-2). The following GPC measurement results were obtained: Mw=8,500and Mw/Mn=1.05.

[Polymer Synthesis Example 5] Synthesis of Polymers (VIb) to (VIf)

Polymers (VIb) to (VIf) were synthesized by approximately the sameoperations as in the [Polymer Synthesis Example 1], except that theamount of the polymerization initiator (Va) used (1.05 mmol/g THFsolution) was changed. The analysis results are shown in Table 2.

TABLE 2 Polymerization initiator (Va) Mw/ amount (g) Mw Mn Polymer (VIa)4.96 8,500 1.04 Polymer (VIb) 4.50 9,400 1.05 Polymer (VIc) 4.00 10,5001.06 Polymer (VId) 3.50 12,000 1.05 Polymer (VIe) 3.00 14,000 1.06Polymer (VIf) 2.50 16,900 1.05

[Polymer Synthesis Example 6] Synthesis of Polymers (IIb) to (IIf)

Polymers (IIb) to (IIf) were synthesized by approximately the sameoperations as in the [Polymer Synthesis Example 2], except that thepolymer (VIa) as a starting raw material was changed to the polymers(VIb) to (VIf). The analysis results are shown in Table 3.

TABLE 3 Starting Mw/ raw material Mw Mn polymer Polymer (IIa) 8,800 1.04Polymer (VIa) Polymer (IIb) 9,600 1.05 Polymer (VIb) Polymer (IIc)10,800 1.06 Polymer (VIc) Polymer (IId) 12,300 1.05 Polymer (VId)Polymer (IIe) 14,200 1.06 Polymer (VIe) Polymer (IIf) 17,100 1.05Polymer (VIf)

[Polymer Synthesis Example 7] Synthesis of Polymers (IIIb) to (IIIf)

Polymers (IIIb) to (IIIf) were synthesized by approximately the sameoperations as in the [Polymer Synthesis Example 3] and the [PolymerSynthesis Example 4], except that the polymer (IIa) as a starting rawmaterial was changed to the polymers (IIb) to (IIf). The analysisresults are shown in Table 4.

TABLE 4 Mw/ Starting raw material Mw Mn polymer Polymer (IIIa) 8,5001.05 Polymer (IIa) Polymer (IIIb) 9,400 1.05 Polymer (IIb) Polymer(IIIc) 10,500 1.06 Polymer (IIc) Polymer (IIId) 12,100 1.05 Polymer(IId) Polymer (IIIe) 14,000 1.06 Polymer (IIe) Polymer (IIIf) 16,8001.05 Polymer (IIf)

[Polymer Synthesis Example 8] Synthesis of Polymers (IIIg) to (IIIn)

Polymers (IIIg) to (IIIn) were synthesized by approximately the sameoperations as in the [Polymer Synthesis Example 1] to the [PolymerSynthesis Example 4], except that the deprotection condition was changedby changing the electrophile from (Ia) to (Ib) to (Ii) in the [PolymerSynthesis Example 2]. The deprotection in the case in which theelectrophiles (Ib) to (Ie), and (Ii) were used was performed in the samemanner as in the Polymer Synthesis Example 3. The deprotection in thecase in which electrophiles (If) and (Ih) were used was performed underthe condition of Birch reduction in which liquid ammonium and metalsodium were used. The deprotection in the case in which the electrophile(Ig) was used was performed by reacting a hydrazine hydrate in analcohol. The analysis results are shown in Table 5.

TABLE 5 Mw Mw/Mn Electrophile used Polymer (IIIg) 8,500 1.05 Ib Polymer(IIIh) 8,500 1.05 Ic Polymer (IIIi) 8,500 1.05 Id Polymer (IIIj) 8,6001.06 Ie Polymer (IIIk) 8,600 1.05 If Polymer (IIIl) 8,500 1.06 IgPolymer (IIIm) 8,700 1.05 Ih Polymer (IIIn) 8,700 1.05 Ii

[Comparative Polymer Synthesis Example 1] Synthesis of Polymer (IXa)

A stirring bar and 71 mg (1.01 mmol) of potassium methoxide (made byKanto Chemical Co., Ltd.) as a polymerization initiator was placed in a500 mL four neck round-bottom flask connected to a thermometer, adripping funnel, and a Dimroth condenser. After the degree of vacuum inthe device was held at 10 Pa or less, the internal part of the devicewas heated with an oil bath and a heat gun, so that the water content inthe system was removed.

Subsequently 40 μL (1.00 mmol) of methanol (made by Tokyo ChemicalIndustry Co., Ltd.) and 140 g of distilled THF were injected in the fourneck flask under nitrogen stream, and the mixture was stirred at roomtemperature until potassium methoxide was completely dissolved. Theratio of the amounts of substances between potassium methoxide being thepolymerization initiator synthesized by the above-described method andmethanol being the alcohol as an initiator raw material is 50:50 (mol%).

Into the dripping funnel, a mixed solution of 35 g of ethylene oxide and60 g of distilled THF were injected, to be dripped into the four neckflask slowly, with the inner temperature being held at 35° C. or lower.After dripping of the entire quantity, the mixture was stirred for 80hours, with the inner temperature being held at 50° C. or lower.

After confirming no change in conversion ratio of ethylene oxide, 0.06 gof acetic acid was added into the flask. After removal of ethylene oxideby nitrogen bubbling, the reaction liquid was transferred into a 500 mLround-bottom flask, and concentrated until solid precipitated with arotary evaporator. The crude product of polymer in an amount of 23 g wasredissolved in 46 g of toluene, and transferred into a dripping funnel.

Into a 500 mL beaker with a stirring bar therein, 138 g of isopropylether was injected. After dripping of the polymer solution for 10minutes with a dripping funnel, maturation was performed for 20 minutes.The produced white powder was filtered and returned to the originalbeaker, to be washed with a mixed solvent of 69 g of isopropyl ether for20 minutes. The same washing operation was further performed twice. Areaction scheme is shown in the following.

The produced white powder was vacuum-dried to obtain 18.54 g of acomparative polymer (IXa). The following GPC measurement results wereobtained: Mw=7,200 and Mw/Mn=1.16.

[Comparative Polymer Synthesis Example 2] Synthesis of Polymer (Xa)

A stirring bar was placed in a 500 mL four neck flask connected to athermometer, a Dimroth condenser, a fractionating column, and a 300 mLround-bottom flask. After the degree of vacuum in the device was held at10 Pa or less, the internal part of the device was heated with an oilbath and a heat gun, so that the water content in the system wasremoved. The THF solution of the polymer (VIa) (10 g in terms of solidcontent) was fractionated with a syringe and fed into the 500 mL fourneck flask under nitrogen stream. With the temperature in the 500 mLfour neck flask being held at 40° C. or lower, the polymer solution wasconcentrated and adjusted to be a solid content concentration of 25 wt.%.

Under a nitrogen stream, 1.0 g of acrylonitrile was fed in the 500 mLfour neck flask, so that maturation was performed for 3 hours, with thetemperature in the 500 mL four neck flask being held at 40° C. Aftercompletion of the reaction, the oil bath was detached and the reactionsystem was cooled to room temperature. After addition of 0.2 g of aceticacid into the system for quenching, 10 g of an alkali adsorbent “KYOWADO700” (made by Kyowa Chemical Industry Co., Ltd.) was added forperforming a reaction for 3 hours. After filtration of the alkaliadsorbent, the filtrate was transferred into a 300 mL round-bottom flaskand concentrated to a solid content concentration of a comparativepolymer (Xa) of 25 wt. % with a rotary evaporator.

In a 500 mL beaker with a stirring bar therein, 100 g of hexane and 50 gof ethyl acetate were mixed. After dripping of the concentrated liquidfor 10 minutes with a dripping funnel, maturation was performed for 20minutes. The produced white powder was filtered and then returned to theoriginal beaker, to be washed with a mixed solvent of 50 g of hexane and25 g of ethyl acetate for 20 minutes. The same washing operation wasfurther performed once. A reaction scheme is shown in the following.

The produced white powder was vacuum-dried to obtain 9.12 g of acomparative polymer (Xa). The following GPC measurement results wereobtained: Mw=8,800 and Mw/Mn=1.05.

[Comparative Polymer Synthesis Example 3] Synthesis of Polymer (IIIo)

Into a 500 mL autoclave for hydrogen reduction, 5.0 g of a polymer (Xa),5.0 g of Raney cobalt catalyst R-400 (made by Nikko Rica Corporation),45.0 g of methanol, and 3.5 mL of 1 N methanol solution of ammonia (madeby Aldrich) were injected at room temperature. Subsequently hydrogen gas(pressure: 10 kg/cm²) was enclosed, and the inner temperature was raisedto 120° C. for a direct reaction for 6 hours. After cooling to roomtemperature, the pressure was returned to atmospheric pressure.Subsequently nitrogen was blown in for removal of ammonia in the system.After removal of the Raney cobalt catalyst by filtration, the filtratewas transferred into a 100 mL round-bottom flask, and ammonia andmethanol were distilled away with a rotary evaporator. Through vacuumconcentration to dryness, 4.5 g of a mixture of a polymer (IIIo) and thecompounds represented by the following formula (VIIo) to (IXo) wereobtained. The following GPC measurement results were obtained: Mw=8,900and Mw/Mn=1.11. A reaction scheme and by-products are shown in thefollowing.

Analysis of Content of Impurities in Products Produced in PolymerSynthesis Example 3 and Comparative Polymer Synthesis Example 3

The content of impurities in the product produced in the [PolymerSynthesis Example 3] and in the product produced in the [ComparativePolymer Synthesis Example 3] were analyzed. The results are shown inTable 6 below.

A compound represented by “mPEG” in Table 6 is a compound correspondingto the general formula (IXo) in the [Comparative Polymer SynthesisExample 3] and is a compound produced through β-elimination ofacrylonitrile from a polymer having a cyanoethyl group at an end. Thecompositional ratio of mPEG was calculated by H-NMR measurement. Firstof all, each of the products produced in the [Polymer Synthesis Example3] and in the [Comparative Polymer Synthesis Example 3] was weighed by10 mg, and each of these is dissolved in 0.75 ml of CDCl3, then 50 mg oftrifluoroacetic anhydride was added thereto, and after the resultantmixture was left standing for 1 day, the measurement was conducted. Thecompositional ratio of mPEG was calculated from the ratio between aproton originated from α-methylene of an ester in the compoundrepresented by the general formula (IX-1) produced through the treatmentand a proton originated from a-methylene of an amide in the compoundrepresented by the general formula (III-1) also produced from thetreatment.

Compounds represented by “secondary and tertiary amines” in Table 6 arecompounds corresponding to the general formulas (VIIo) and (VIIIo) inthe [Comparative Polymer Synthesis Example 3] respectively. The amountof the compounds mixed was measured by GPC and was calculated from thearea percentages of the polymers having twice or three times as large asthe molecular weight.

From these results, β-elimination of acrylonitrile and production ofsecondary and tertiary amines due to hydrogen reduction were observed inthe comparative polymer (IIIo); however, these by-products were notobserved in the example polymer (IIIa).

TABLE 6 Secondary and mPEG tertiary amines Polymer (IIIa)  <1% <1%Comparative polymer (IIIo)   10%   5%

Metal Analysis of Products Produced in Polymer Synthesis Examples 3 and4, and Comparative Polymer Synthesis Example 3

Metal impurities in the products produced in each of the [PolymerSynthesis Example 3] and the [Polymer Synthesis Example 4], and in theproduct produced in the [Comparative Synthesis Example 3] were analyzedwith a high frequency inductively coupled plasma mass spectrometer(ICP-MS, Agilent Technologies 7500 cs). The analysis was performed by astandard loaded method using samples each obtained by diluting a polymerwith ultrapure water by 100 times for measurement. The analysis results(value obtained in terms of solid content) are shown in Table 7 (inunits of ppb).

As a result of the metal analysis, it is revealed that the heavy metalused for reduction is mixed in the comparative polymer (IIIo), but thata heavy metal is not contained in the polymers (IIIa) and (IIIa-2) ofthe Examples because a heavy metal catalyst is not used in the synthesisprocess.

TABLE 7 Co Ni Pd Pt Rh Ru Cu Cr K Polymer <1 <1 <1 <1 <1 <1 <1 <1 7000(IIIa) Polymer <1 <1 <1 <1 <1 <1 <1 <1 100 (IIIa-2) Comparative 200 <1<1 <1 <1 <1 <1 <1 8000 polymer (IIIo)

[Synthesis Example 5] Synthesis of Polymerization Initiators (Vb) to(Vg)

Polymerization initiators (Vb) to (Vg) were synthesized in the samemethod as described in [Synthesis Example 1], except that the rawmaterial alcohol was changed to alcohols in the table below.

TABLE 8 Raw material alcohol Polymerization initiator (Vb) Triethyleneglycol monomethyl ether Polymerization initiator (Vc) Diethylene glycolmonoethyl ether Polymerization initiator (Vd) Triethylene glycolmonoethyl ether Polymerization initiator (Ve) Diethylene glycolmonopropyl ether Polymerization initiator (Vf) Diethylene glycolmono-tert-butyl ether Polymerization initiator (Vg) Triethylene glycolmonocyclohexyl ether

[Comparative Synthesis Example 1] Synthesis of ComparativePolymerization Initiators (Vh) to (Vk)

Comparative polymerization initiators (Vh) to (Vk) were synthesized inthe same method as described in [Synthesis Example 1], except that theraw material alcohol was changed to alcohols in the table below.

TABLE 9 Raw material alcohol Comparative polymerization initiator (Vh)Methanol Comparative polymerization initiator (Vi) Ethanol Comparativepolymerization initiator (Vj) 1-Propanol Comparative polymerizationinitiator (Vk) Cyclohexanol

Comparison of Solubility of Polymerization Initiators Produced inSynthesis Examples 1 and 5, and Comparative Synthesis Example 1 toPolymerization Solvent

Subsequently, the results of the solubility of the polymerizationinitiators (Va) to (Vg) and the comparative polymerization initiators(Vh) to (Vk) to the polymerization solvent are shown. The results ofdissolving each polymerization initiator at a concentration of 20 wt. %in THF as a polymerization solvent are shown in the Table 10. Aninitiator for which cloudiness was not observed at all by visualobservation, when dissolved, was denoted as “Excellent”, and aninitiator for which cloudiness was observed, when dissolved, or theinitiator that did not dissolve at all was denoted as “Poor”. As aresult thereof, the initiators (Va) to (Vg), each having a long chain,dissolved in the solvent. On the other hand, the comparative initiators(Vh) to (Vk) did not dissolve in the solvent.

TABLE 10 THF Initiator Va Excellent Vb Excellent Vc Excellent VdExcellent Ve Excellent Vf Excellent Vg Excellent Comparative Vh Poorinitiator Vi Poor Vj Poor Vk Poor

It is revealed that, in the [Polymer Synthesis Example 1] and in the[Comparative Polymer Synthesis Example 1], the latter requires a longpolymerization time, as long as 80 hours, due to the presence of analcohol as an initiator raw material, and that, in the former, thepolymerization reaction is completed within 8 hours by using aninitiator that is soluble in THF even when the amount of residualalcohol as an initiator raw material is small. That is to say, thepolymerization of an alkylene oxide under mild conditions was realizedby the method of the present invention. Moreover, by using the reactionliquid in the [Polymer Synthesis Example 1] directly to the reaction inthe [Polymer Synthesis Example 2], the process was able to besubstantially simplified. Furthermore, by using an organic solvent forpurifying a resin with an ion exchange resin in [Polymer SynthesisExample 4], it became possible to purify a polymer by a simple methodwithout using freeze dry in the final process.

Hydrogenation reaction using a heavy metal as a catalyst is required forreducing a cyano group in the [Comparative Polymer Synthesis Examples 2and 3]; however, in the [Polymer Synthesis Examples 2 and 3], theelectrophiles the amino group of which is protected by a protectinggroup are used, and therefore the intended polymers were able to besynthesized only by performing deprotection. In the comparative polymer(IIIo), 3-Elimination of acrylonitrile and production of secondary andtertiary amines due to hydrogen reduction occurred; however, in theexample polymer (IIIa), production of any one of the amines were notobserved (Table 6).

Moreover, from the results of metal analysis, it is revealed that, inthe [Polymer Synthesis Examples 3 and 4] and in the [Comparative PolymerSynthesis Example 3], the heavy metal used for reduction is mixed in thecomparative polymer (IIIo), but that a heavy metal is not substantiallymixed in the example polymers (IIIa and IIIa-2) because no heavy metalis used in [Synthesis Examples 3 and 4] (Table 7). Moreover, the amountof a K metal mixed was able to be reduced by the purification with astrong acid cation exchange resin. As a result thereof, synthesis of anamino group-containing narrowly distributed polyalkylene glycolderivative without mixing of a heavy metal having a possibility thatcauses adverse influence in medical supplies was able to be achieved bythe present invention. Moreover, in the present invention,polymerization of an alkylene oxide, terminal-stopping reaction with anelectrophile, and subsequent deprotection may be performed continuously,so that the simplification of the process was also achieved.

The method for producing an amino group-containing narrowly distributedand high-purity polyalkylene glycol derivative of the present inventionprovides a raw material of block copolymers for use in medical suppliesand cosmetic products.

Having thus described certain embodiments of the present invention, itis to be understood that the invention defined by the appended claims isnot to be limited by particular details set forth in the abovedescription as many apparent variations thereof are possible withoutdeparting from the spirit or scope thereof as hereinafter claimed.

1.-22. (canceled)
 23. An electrophile of formula (I):

wherein R_(A) ^(1a) and R_(A) ^(1b) each independently representSi(R¹)₃, wherein each R₁ independently represents a linear monovalenthydrocarbon group having 1 to 6 carbon atoms, or a branched or cyclicmonovalent hydrocarbon group having 3 to 6 carbon atoms, and each R₁ maybind to each other to form a 3 to 6 membered ring together with asilicon atom having bonds with R¹; R_(A) ² represents a linear divalenthydrocarbon group having 1 to 6 carbon atoms, or a branched or cyclicdivalent hydrocarbon group having 3 to 6 carbon atoms; and X representsa leaving group.
 24. The electrophile according to claim 23, wherein Xis p-toluenesulfonate, methanesulfonate or trifluoromethanesulfonate.25. An alcohol compound having silyl-protected amino group of formula(I-2-A):

wherein R¹ each independently represent a linear monovalent hydrocarbongroup having 1 to 6 carbon atoms, or a branched or cyclic monovalenthydrocarbon group having 3 to 6 carbon atoms, and R¹ may bind to eachother to form a 3 to 6 membered ring together with a silicon atom havingbonds with R¹; and R_(A) ² represents a linear divalent hydrocarbongroup having 1 to 6 carbon atoms, or a branched or cyclic divalenthydrocarbon group having 3 to 6 carbon atoms.
 26. A method for producingthe alcohol compound having silyl-protected amino group of formula(I-2-A) according to claim 25, comprising: protecting an amino group ofan aminoalkyl compound of formula (I-0-A) with two trialkylsilyl groupsof Si(R¹)₃, and protecting a hydroxyl group of the compound of formula(I-0-A) with a trialkylsilyl group of Si(R¹)₃ to obtain a trisilylcompound of formula (I-1-A):HO—R_(A) ²—NH₂  (I-0-A) wherein R_(A) ² is the same as R_(A) ² informula (I-2-A);

wherein R¹ and R_(A) ² are the same as R¹ and R_(A) ² in formula(I-2-A); and removing only the trialkylsilyl group which protects thehydroxyl group from the compound of formula (I-1-A).
 27. The methodaccording to claim 26, wherein the group of Si(R¹)₃ is independentlyselected from a trimethylsilyl group, a triethylsilyl group, and atert-butyldimethylsilyl group.
 28. A method for producing theelectrophile of formula (I):

wherein R_(A) ^(1a) and R_(A) ^(1b) each independently representSi(R¹)₃, wherein each R₁ independently represents a linear monovalenthydrocarbon group having 1 to 6 carbon atoms, or a branched or cyclicmonovalent hydrocarbon group having 3 to 6 carbon atoms, and each R₁ maybind to each other to form a 3 to 6 membered ring together with asilicon atom having bonds with R₁; R_(A) ² represents a linear divalenthydrocarbon group having 1 to 6 carbon atoms, or a branched or cyclicdivalent hydrocarbon group having 3 to 6 carbon atoms; and X representsa leaving group, said method comprising: reacting the alcohol compoundhaving silyl-protected amino group of formula (I-2-A) according to claim25 with a sulfonic halide.
 29. The method according to claim 28, whereinthe sulfonic halide is p-toluenesulfonyl chloride or methanesulfonylchloride.